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04.04.2021 | Non-Thematic Review

Mucins reprogram stemness, metabolism and promote chemoresistance during cancer progression

verfasst von: Saravanakumar Marimuthu, Sanchita Rauth, Koelina Ganguly, Chunmeng Zhang, Imayavaramban Lakshmanan, Surinder K. Batra, Moorthy P. Ponnusamy

Erschienen in: Cancer and Metastasis Reviews | Ausgabe 2/2021

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Abstract

Mucins are high-molecular-weight glycoproteins dysregulated in aggressive cancers. The role of mucins in disease progression, tumor proliferation, and chemotherapy resistance has been studied extensively. This article provides a comprehensive review of mucin’s function as a physical barrier and the implication of mucin overexpression in impeded drug delivery to solid tumors. Mucins regulate the epithelial to mesenchymal transition (EMT) of cancer cells via several canonical and non-canonical oncogenic signaling pathways. Furthermore, mucins play an extensive role in enriching and maintaining the cancer stem cell (CSC) population, thereby sustaining the self-renewing and chemoresistant cellular pool in the bulk tumor. It has recently been demonstrated that mucins regulate the metabolic reprogramming during oncogenesis and cancer progression, which account for tumor cell survival, proliferation, and drug-resistance. This review article focuses on delineating mucin’s role in oncogenic signaling and aberrant regulation of gene expressions, culminating in CSC maintenance, metabolic rewiring, and development of chemoresistance, tumor progression, and metastasis.

van Putten, J. P. M., & Strijbis, K. (2017). Transmembrane mucins: Signaling receptors at the intersection of inflammation and cancer. Journal of Innate Immunity, 9(3), 281–299. https://doi.org/10.1159/000453594.CrossRefPubMedPubMedCentral

Forstner, J. F. (1978). Intestinal mucins in health and disease. Digestion, 17(3), 234–263. https://doi.org/10.1159/000198115.CrossRefPubMed

Kaur, S., Kumar, S., Momi, N., Sasson, A. R., & Batra, S. K. (2013). Mucins in pancreatic cancer and its microenvironment. Nature Reviews. Gastroenterology & Hepatology, 10(10), 607–620. https://doi.org/10.1038/nrgastro.2013.120.CrossRef

Chaturvedi, P., Singh, A. P., & Batra, S. K. (2008). Structure, evolution, and biology of the MUC4 mucin. The FASEB Journal, 22(4), 966–981. https://doi.org/10.1096/fj.07-9673rev.CrossRefPubMed

Dhanisha, S. S., Guruvayoorappan, C., Drishya, S., & Abeesh, P. (2018). Mucins: Structural diversity, biosynthesis, its role in pathogenesis and as possible therapeutic targets. Critical Reviews in Oncology/Hematology, 122, 98–122. https://doi.org/10.1016/j.critrevonc.2017.12.006.CrossRefPubMed

Krishn, S. R., Ganguly, K., Kaur, S., & Batra, S. K. (2018). Ramifications of secreted mucin MUC5AC in malignant journey: A holistic view. Carcinogenesis, 39(5), 633–651. https://doi.org/10.1093/carcin/bgy019.CrossRefPubMedPubMedCentral

Ganguly, K., Rauth, S., Marimuthu, S., Kumar, S., & Batra, S. K. (2020). Unraveling mucin domains in cancer and metastasis: When protectors become predators. Cancer Metastasis Reviews, 39(3), 647–659. https://doi.org/10.1007/s10555-020-09896-5.CrossRefPubMed

Lakshmanan, I., Ponnusamy, M. P., Macha, M. A., Haridas, D., Majhi, P. D., Kaur, S., Jain, M., Batra, S. K., & Ganti, A. K. (2015). Mucins in lung cancer: Diagnostic, prognostic, and therapeutic implications. Journal of Thoracic Oncology, 10(1), 19–27. https://doi.org/10.1097/jto.0000000000000404.CrossRefPubMed

Pothuraju, R., Krishn, S. R., Gautam, S. K., Pai, P., Ganguly, K., Chaudhary, S., Rachagani, S., Kaur, S., & Batra, S. K. (2020). Mechanistic and functional shades of mucins and associated glycans in colon cancer. Cancers (Basel), 12(3). https://doi.org/10.3390/cancers12030649.

10.

Gautam, S. K., Kumar, S., Dam, V., Ghersi, D., Jain, M., & Batra, S. K. (2020). MUCIN-4 (MUC4) is a novel tumor antigen in pancreatic cancer immunotherapy. Seminars in Immunology, 47, 101391. https://doi.org/10.1016/j.smim.2020.101391.CrossRefPubMedPubMedCentral

11.

Bafna, S., Kaur, S., & Batra, S. K. (2010). Membrane-bound mucins: the mechanistic basis for alterations in the growth and survival of cancer cells. Oncogene, 29(20), 2893–2904. https://doi.org/10.1038/onc.2010.87.CrossRefPubMedPubMedCentral

12.

Rao, C. V., Janakiram, N. B., & Mohammed, A. (2017). Molecular pathways: Mucins and drug delivery in cancer. Clinical Cancer Research, 23(6), 1373–1378. https://doi.org/10.1158/1078-0432.Ccr-16-0862.CrossRefPubMed

13.

Moniaux, N., Escande, F., Porchet, N., Aubert, J. P., & Batra, S. K. (2001). Structural organization and classification of the human mucin genes. Frontiers in Bioscience, 6, D1192–D1206. https://doi.org/10.2741/moniaux.CrossRefPubMed

14.

Messager, M., Lefevre, J. H., Pichot-Delahaye, V., Souadka, A., Piessen, G., & Mariette, C. (2011). The impact of perioperative chemotherapy on survival in patients with gastric signet ring cell adenocarcinoma: A multicenter comparative study. Annals of Surgery, 254(5), 684–693; discussion 693. https://doi.org/10.1097/SLA.0b013e3182352647.CrossRefPubMed

15.

Leal, J., Smyth, H. D. C., & Ghosh, D. (2017). Physicochemical properties of mucus and their impact on transmucosal drug delivery. International Journal of Pharmaceutics, 532(1), 555–572. https://doi.org/10.1016/j.ijpharm.2017.09.018.CrossRefPubMedPubMedCentral

16.

Bhat, P. G., Flanagan, D. R., & Donovan, M. D. (1996). Drug diffusion through cystic fibrotic mucus: Steady-state permeation, rheologic properties, and glycoprotein morphology. Journal of Pharmaceutical Sciences, 85(6), 624–630. https://doi.org/10.1021/js950381s.CrossRefPubMed

17.

Suh, H., Pillai, K., & Morris, D. L. (2017). Mucins in pancreatic cancer: Biological role, implications in carcinogenesis and applications in diagnosis and therapy. American Journal of Cancer Research, 7(6), 1372–1383.PubMedPubMedCentral

18.

Kalra, A. V., & Campbell, R. B. (2009). Mucin overexpression limits the effectiveness of 5-FU by reducing intracellular drug uptake and antineoplastic drug effects in pancreatic tumours. European Journal of Cancer, 45(1), 164–173. https://doi.org/10.1016/j.ejca.2008.10.008.CrossRefPubMed

19.

Shaw, L. R., Irwin, W. J., Grattan, T. J., & Conway, B. R. (2005). The influence of excipients on the diffusion of ibuprofen and paracetamol in gastric mucus. International Journal of Pharmaceutics, 290(1-2), 145–154. https://doi.org/10.1016/j.ijpharm.2004.11.028.CrossRefPubMed

20.

Sigurdsson, H. H., Kirch, J., & Lehr, C. M. (2013). Mucus as a barrier to lipophilic drugs. International Journal of Pharmaceutics, 453(1), 56–64. https://doi.org/10.1016/j.ijpharm.2013.05.040.CrossRefPubMed

21.

Jonckheere, N., Skrypek, N., & Van Seuningen, I. (2014). Mucins and tumor resistance to chemotherapeutic drugs. Biochimica et Biophysica Acta, 1846(1), 142–151. https://doi.org/10.1016/j.bbcan.2014.04.008.CrossRefPubMed

22.

Jentoft, N. (1990). Why are proteins O-glycosylated? Trends in Biochemical Sciences, 15(8), 291–294. https://doi.org/10.1016/0968-0004(90)90014-3.CrossRefPubMed

23.

van de Wiel-van Kemenade, E., Ligtenberg, M. J., de Boer, A. J., Buijs, F., Vos, H. L., Melief, C. J., Hilkens, J., & Figdor, C. G. (1993). Episialin (MUC1) inhibits cytotoxic lymphocyte-target cell interaction. Journal of Immunology, 151(2), 767–776.

24.

Bhatia, R., Gautam, S. K., Cannon, A., Thompson, C., Hall, B. R., Aithal, A., Banerjee, K., Jain, M., Solheim, J. C., Kumar, S., & Batra, S. K. (2019). Cancer-associated mucins: role in immune modulation and metastasis. Cancer Metastasis Reviews, 38(1-2), 223–236. https://doi.org/10.1007/s10555-018-09775-0.CrossRefPubMedPubMedCentral

25.

Hollingsworth, M. A., & Swanson, B. J. (2004). Mucins in cancer: Protection and control of the cell surface. Nature Reviews. Cancer, 4(1), 45–60. https://doi.org/10.1038/nrc1251.CrossRefPubMed

26.

Nath, S., & Mukherjee, P. (2014). MUC1: A multifaceted oncoprotein with a key role in cancer progression. Trends in Molecular Medicine, 20(6), 332–342. https://doi.org/10.1016/j.molmed.2014.02.007.CrossRefPubMedPubMedCentral

27.

Nath, S., Daneshvar, K., Roy, L. D., Grover, P., Kidiyoor, A., Mosley, L., Sahraei, M., & Mukherjee, P. (2013). MUC1 induces drug resistance in pancreatic cancer cells via upregulation of multidrug resistance genes. Oncogenesis, 2(6), e51. https://doi.org/10.1038/oncsis.2013.16.CrossRefPubMedPubMedCentral

28.

Pitroda, S. P., Khodarev, N. N., Beckett, M. A., Kufe, D. W., & Weichselbaum, R. R. (2009). MUC1-induced alterations in a lipid metabolic gene network predict response of human breast cancers to tamoxifen treatment. Proceedings of the National Academy of Sciences of the United States of America, 106(14), 5837–5841. https://doi.org/10.1073/pnas.0812029106.CrossRefPubMedPubMedCentral

29.

Jin, W., Liao, X., Lv, Y., Pang, Z., Wang, Y., Li, Q., Liao, Y., Ye, Q., Chen, G., Zhao, K., & Huang, L. (2017). MUC1 induces acquired chemoresistance by upregulating ABCB1 in EGFR-dependent manner. Cell Death & Disease, 8(8), e2980. https://doi.org/10.1038/cddis.2017.378.CrossRef

30.

Ham, S. Y., Kwon, T., Bak, Y., Yu, J. H., Hong, J., Lee, S. K., Yu, D. Y., & Yoon, D. Y. (2016). Mucin 1-mediated chemoresistance in lung cancer cells. Oncogenesis, 5(1), e185. https://doi.org/10.1038/oncsis.2015.47.CrossRefPubMedPubMedCentral

31.

Hagmann, W., Jesnowski, R., & Löhr, J. M. (2010). Interdependence of gemcitabine treatment, transporter expression, and resistance in human pancreatic carcinoma cells. Neoplasia, 12(9), 740–747. https://doi.org/10.1593/neo.10576.CrossRefPubMedPubMedCentral

32.

Wang, W., Abbruzzese, J. L., Evans, D. B., Larry, L., Cleary, K. R., & Chiao, P. J. (1999). The nuclear factor-kappa B RelA transcription factor is constitutively activated in human pancreatic adenocarcinoma cells. Clinical Cancer Research, 5(1), 119–127.PubMed

33.

Arlt, A., Gehrz, A., Müerköster, S., Vorndamm, J., Kruse, M. L., Fölsch, U. R., & Schäfer, H. (2003). Role of NF-kappaB and Akt/PI3K in the resistance of pancreatic carcinoma cell lines against gemcitabine-induced cell death. Oncogene, 22(21), 3243–3251. https://doi.org/10.1038/sj.onc.1206390.CrossRefPubMed

34.

Skrypek, N., Duchêne, B., Hebbar, M., Leteurtre, E., van Seuningen, I., & Jonckheere, N. (2013). The MUC4 mucin mediates gemcitabine resistance of human pancreatic cancer cells via the Concentrative Nucleoside Transporter family. Oncogene, 32(13), 1714–1723. https://doi.org/10.1038/onc.2012.179.CrossRefPubMed

35.

Singh, A. P., Moniaux, N., Chauhan, S. C., Meza, J. L., & Batra, S. K. (2004). Inhibition of MUC4 expression suppresses pancreatic tumor cell growth and metastasis. Cancer Research, 64(2), 622–630. https://doi.org/10.1158/0008-5472.can-03-2636.CrossRefPubMed

36.

Carraway, K. L., Perez, A., Idris, N., Jepson, S., Arango, M., Komatsu, M., Haq, B., Price-Schiavi A., Zhang, J., & Carraway, C. (2002). Muc4/sialomucin complex, the intramembrane ErbB2 ligand, in cancer and epithelia: To protect and to survive. Progress in Nucleic Acid Research and Molecular Biology, 71, 149–185. https://doi.org/10.1016/s0079-6603(02)71043-x.

37.

Chaturvedi, P., Singh, A. P., Chakraborty, S., Chauhan, S. C., Bafna, S., Meza, J. L., Singh, P. K., Hollingsworth, M. A., Mehta, P. P., & Batra, S. K. (2008). MUC4 mucin interacts with and stabilizes the HER2 oncoprotein in human pancreatic cancer cells. Cancer Research, 68(7), 2065–2070. https://doi.org/10.1158/0008-5472.Can-07-6041.CrossRefPubMedPubMedCentral

38.

Ramsauer, V. P., Pino, V., Farooq, A., Carothers Carraway, C. A., Salas, P. J., & Carraway, K. L. (2006). Muc4-ErbB2 complex formation and signaling in polarized CACO-2 epithelial cells indicate that Muc4 acts as an unorthodox ligand for ErbB2. Molecular Biology of the Cell, 17(7), 2931–2941. https://doi.org/10.1091/mbc.e05-09-0895.CrossRefPubMedPubMedCentral

39.

Park, S. H., Lee, J. H., Berek, J. S., & Hu, M. C. (2014). Auranofin displays anticancer activity against ovarian cancer cells through FOXO3 activation independent of p53. International Journal of Oncology, 45(4), 1691–1698. https://doi.org/10.3892/ijo.2014.2579.CrossRefPubMedPubMedCentral

40.

Bae, J. S., Lee, J., Park, Y., Park, K., Kim, J. R., Cho, D. H., Jang, K. Y., & Park, S. H. (2017). Attenuation of MUC4 potentiates the anticancer activity of auranofin via regulation of the Her2/Akt/FOXO3 pathway in ovarian cancer cells. Oncology Reports, 38(4), 2417–2425. https://doi.org/10.3892/or.2017.5853.CrossRefPubMed

41.

Pothuraju, R., Rachagani, S., Krishn, S. R., Chaudhary, S., Nimmakayala, R. K., Siddiqui, J. A., Ganguly, K., Lakshmanan, I., Cox, J. L., Mallya, K., Kaur, S., & Batra, S. K. (2020). Molecular implications of MUC5AC-CD44 axis in colorectal cancer progression and chemoresistance. Molecular Cancer, 19(1), 37. https://doi.org/10.1186/s12943-020-01156-y.CrossRefPubMedPubMedCentral

42.

Sheng, Y., Ng, C. P., Lourie, R., Shah, E. T., He, Y., Wong, K. Y., Seim, I., Oancea, I., Morais, C., Jeffery, P. L., Hooper, J., Gobe, G. C., & McGuckin, M. A. (2017). MUC13 overexpression in renal cell carcinoma plays a central role in tumor progression and drug resistance. International Journal of Cancer, 140(10), 2351–2363. https://doi.org/10.1002/ijc.30651.CrossRefPubMed

43.

Xu, Z., Liu, Y., Yang, Y., Wang, J., Zhang, G., Liu, Z., Fu, H., Wang, Z., Liu, H., & Xu, J. (2017). High expression of Mucin13 associates with grimmer postoperative prognosis of patients with non-metastatic clear-cell renal cell carcinoma. Oncotarget, 8(5), 7548–7558. https://doi.org/10.18632/oncotarget.13692.

44.

Lakshmanan, I., Salfity, S., Seshacharyulu, P., Rachagani, S., Thomas, A., Das, S., Majhi, P. D., Nimmakayala, R. K., Vengoji, R., Lele, S. M., Ponnusamy, M. P., Batra, S. K., & Ganti, A. K. (2017). MUC16 regulates TSPYL5 for lung cancer cell growth and chemoresistance by suppressing p53. Clinical Cancer Research, 23(14), 3906–3917. https://doi.org/10.1158/1078-0432.Ccr-16-2530.CrossRefPubMedPubMedCentral

45.

Das, S., Rachagani, S., Torres-Gonzalez, M. P., Lakshmanan, I., Majhi, P. D., Smith, L. M., Wagner, K., & Batra, S. K. (2015). Carboxyl-terminal domain of MUC16 imparts tumorigenic and metastatic functions through nuclear translocation of JAK2 to pancreatic cancer cells. Oncotarget, 6(8), 5772–5787. https://doi.org/10.18632/oncotarget.3308.

46.

Boivin, M., Lane, D., Piché, A., & Rancourt, C. (2009). CA125 (MUC16) tumor antigen selectively modulates the sensitivity of ovarian cancer cells to genotoxic drug-induced apoptosis. Gynecologic Oncology, 115(3), 407–413. https://doi.org/10.1016/j.ygyno.2009.08.007.CrossRefPubMed

47.

Weissman, I. L. (2000). Stem cells: units of development, units of regeneration, and units in evolution. Cell, 100(1), 157–168. https://doi.org/10.1016/s0092-8674(00)81692-x.CrossRefPubMed

48.

Zhao, W., Ji, X., Zhang, F., Li, L., & Ma, L. (2012). Embryonic stem cell markers. Molecules, 17(6), 6196–6236. https://doi.org/10.3390/molecules17066196.CrossRefPubMedPubMedCentral

49.

Yan, Q., Yao, D., Wei, L. L., Huang, Y., Myers, J., Zhang, L., Xin, W., Shim, J., Man, Y., Petryniak, B., Gerson, S., Lowe, J. B., & Zhou, L. (2010). O-fucose modulates Notch-controlled blood lineage commitment. The American Journal of Pathology, 176(6), 2921–2934. https://doi.org/10.2353/ajpath.2010.090702.CrossRefPubMedPubMedCentral

50.

Seth, A., Machingo, Q. J., Fritz, A., & Shur, B. D. (2010). Core fucosylation is required for midline patterning during zebrafish development. Developmental Dynamics, 239(12), 3380–3390. https://doi.org/10.1002/dvdy.22475.CrossRefPubMedPubMedCentral

51.

Greaves, M., & Maley, C. C. (2012). Clonal evolution in cancer. Nature, 481(7381), 306–313. https://doi.org/10.1038/nature10762.CrossRefPubMedPubMedCentral

52.

Gupta, P. B., Onder, T. T., Jiang, G., Tao, K., Kuperwasser, C., Weinberg, R. A., & Lander, E. S. (2009). Identification of selective inhibitors of cancer stem cells by high-throughput screening. Cell, 138(4), 645–659. https://doi.org/10.1016/j.cell.2009.06.034.

53.

Alam, M., Ahmad, R., Rajabi, H., Kharbanda, A., & Kufe, D. (2013). MUC1-C oncoprotein activates ERK → C/EBPβ signaling and induction of aldehyde dehydrogenase 1A1 in breast cancer cells. The Journal of Biological Chemistry, 288(43), 30892–30903. https://doi.org/10.1074/jbc.M113.477158.CrossRefPubMedPubMedCentral

54.

Engelmann, K., Shen, H., & Finn, O. J. (2008). MCF7 side population cells with characteristics of cancer stem/progenitor cells express the tumor antigen MUC1. Cancer Research, 68(7), 2419–2426. https://doi.org/10.1158/0008-5472.Can-07-2249.CrossRefPubMed

55.

Stroopinsky, D., Rosenblatt, J., Ito, K., Mills, H., Yin, L., Rajabi, H., Vasir, B., Kufe, T., Luptakova, K., Arnason, J., Nardella, C., Levine, J. D., Joyce, R. M., Galinsky, I., Reiter, Y., Stone, R. M., Pandolfi, P. P., Kufe, D., & Avigan, D. (2013). MUC1 is a potential target for the treatment of acute myeloid leukemia stem cells. Cancer Research, 73(17), 5569–5579. https://doi.org/10.1158/0008-5472.Can-13-0677.CrossRefPubMedPubMedCentral

56.

Guo, M., Luo, B., Pan, M., Li, M., Xu, H., Zhao, F., & Dou, J. (2020). Colorectal cancer stem cell vaccine with high expression of MUC1 serves as a novel prophylactic vaccine for colorectal cancer. International Immunopharmacology, 88, 106850. https://doi.org/10.1016/j.intimp.2020.106850.CrossRefPubMed

57.

Guo, M., You, C., Dong, W., Luo, B., Wu, Y., Chen, Y., Li, J., Pan, M., Li, M., Zhao, F., & Dou, J. (2020). The surface dominant antigen MUC1 is required for colorectal cancer stem cell vaccine to exert anti-tumor efficacy. Biomedicine & Pharmacotherapy, 132, 110804. https://doi.org/10.1016/j.biopha.2020.110804.CrossRef

58.

Curry, J. M., Thompson, K. J., Rao, S. G., Besmer, D. M., Murphy, A. M., Grdzelishvili, V. Z., Ahrens, W. A., McKillop, I. H., Sindram, D., Iannitti, D. A., Martinie, J. B., & Mukherjee, P. (2013). The use of a novel MUC1 antibody to identify cancer stem cells and circulating MUC1 in mice and patients with pancreatic cancer. Journal of Surgical Oncology, 107(7), 713–722. https://doi.org/10.1002/jso.23316.CrossRefPubMed

59.

Ponnusamy, M. P., Seshacharyulu, P., Vaz, A., Dey, P., & Batra, S. K. (2011). MUC4 stabilizes HER2 expression and maintains the cancer stem cell population in ovarian cancer cells. Journal of Ovarian Research, 4(1), 7. https://doi.org/10.1186/1757-2215-4-7.CrossRefPubMedPubMedCentral

60.

Mimeault, M., Johansson, S. L., Senapati, S., Momi, N., Chakraborty, S., & Batra, S. K. (2010). MUC4 down-regulation reverses chemoresistance of pancreatic cancer stem/progenitor cells and their progenies. Cancer Letters, 295(1), 69–84. https://doi.org/10.1016/j.canlet.2010.02.015.CrossRefPubMedPubMedCentral

61.

Jimeno, A., Feldmann, G., Suárez-Gauthier, A., Rasheed, Z., Solomon, A., Zou, G. M., Rubio-Viqueira, B., García-García, E., López-Ríos, F., Matsui, W., Maitra, A., & Hidalgo, M. (2009). A direct pancreatic cancer xenograft model as a platform for cancer stem cell therapeutic development. Molecular Cancer Therapeutics, 8(2), 310–314. https://doi.org/10.1158/1535-7163.Mct-08-0924.CrossRefPubMedPubMedCentral

62.

Zhou, J., Wang, C. Y., Liu, T., Wu, B., Zhou, F., Xiong, J. X., Wu, H. S., Tao, J., Zhao, G., Yang, M., & Gou, S. M. (2008). Persistence of side population cells with high drug efflux capacity in pancreatic cancer. World Journal of Gastroenterology, 14(6), 925–930. https://doi.org/10.3748/wjg.14.925.CrossRefPubMedPubMedCentral

63.

Ganguly, K., Krishn, S. R., Rachagani, S., Jahan, R., Shah, A., Nallasamy, P., Rauth, S., Atri, P., Cox, J. L., Pothuraju, R., Smith, L. M., Ayala, S., Evans, C., Ponusamy, M. P., Kumar, S., Kaur, S., & Batra, S. K. (2020). Secretory mucin 5 AC promotes neoplastic progression by augmenting KLF4-mediated pancreatic cancer cell stemness. Cancer Research. https://doi.org/10.1158/0008-5472.Can-20-1293.

64.

Zhang, H., Yang, Y., Wang, Y., Gao, X., Wang, W., Liu, H., He, H., Liang, Y., Pan, K., Wu, H., Shi, J., Xue, H., Liang, L., Cai, Z., Fan, Y., & Zhang, Y. (2015). Relationship of tumor marker CA125 and ovarian tumor stem cells: Preliminary identification. Journal of Ovarian Research, 8, 19. https://doi.org/10.1186/s13048-015-0132-8.CrossRefPubMedPubMedCentral

65.

Lim, S., Becker, A., Zimmer, A., Lu, J., Buettner, R., & Kirfel, J. (2013). SNAI1-mediated epithelial-mesenchymal transition confers chemoresistance and cellular plasticity by regulating genes involved in cell death and stem cell maintenance. PLoS One, 8(6), e66558. https://doi.org/10.1371/journal.pone.0066558.CrossRefPubMedPubMedCentral

66.

Yamada, S., Fuchs, B. C., Fujii, T., Shimoyama, Y., Sugimoto, H., Nomoto, S., Takeda, S., Tanabe, K. K., Kodera, Y., & Nakao, A. (2013). Epithelial-to-mesenchymal transition predicts prognosis of pancreatic cancer. Surgery, 154(5), 946–954. https://doi.org/10.1016/j.surg.2013.05.004.CrossRefPubMed

67.

Comamala, M., Pinard, M., Thériault, C., Matte, I., Albert, A., Boivin, M., Beaudin, J., Piché, A., & Rancourt, C. (2011). Downregulation of cell surface CA125/MUC16 induces epithelial-to-mesenchymal transition and restores EGFR signalling in NIH:OVCAR3 ovarian carcinoma cells. British Journal of Cancer, 104(6), 989–999. https://doi.org/10.1038/bjc.2011.34.CrossRefPubMedPubMedCentral

68.

Horn, G., Gaziel, A., Wreschner, D. H., Smorodinsky, N. I., & Ehrlich, M. (2009). ERK and PI3K regulate different aspects of the epithelial to mesenchymal transition of mammary tumor cells induced by truncated MUC1. Experimental Cell Research, 315(8), 1490–1504. https://doi.org/10.1016/j.yexcr.2009.02.011.CrossRefPubMed

69.

Roy, L. D., Sahraei, M., Subramani, D. B., Besmer, D., Nath, S., Tinder, T. L., Bajaj, E., Shanmugam, K., Lee, Y. Y., Hwang, S. I. L., Gendler, S. J., & Mukherjee, P. (2011). MUC1 enhances invasiveness of pancreatic cancer cells by inducing epithelial to mesenchymal transition. Oncogene, 30(12), 1449–1459. https://doi.org/10.1038/onc.2010.526.CrossRefPubMed

70.

Ponnusamy, M. P., Lakshmanan, I., Jain, M., Das, S., Chakraborty, S., Dey, P., & Batra, S. K. (2010). MUC4 mucin-induced epithelial to mesenchymal transition: A novel mechanism for metastasis of human ovarian cancer cells. Oncogene, 29(42), 5741–5754. https://doi.org/10.1038/onc.2010.309.CrossRefPubMedPubMedCentral

71.

Lakshmanan, I., Rachagani, S., Hauke, R., Krishn, S. R., Paknikar, S., Seshacharyulu, P., Karmakar, S., Nimmakayala, R. K., Kaushik, G., Johansson, S. L., Carey, G. B., Ponnusamy, M. P., Kaur, S., Batra, S. K., & Ganti, A. K. (2016). MUC5AC interactions with integrin β4 enhances the migration of lung cancer cells through FAK signaling. Oncogene, 35(31), 4112–4121. https://doi.org/10.1038/onc.2015.478.CrossRefPubMedPubMedCentral

72.

Hata, T., Rajabi, H., Yamamoto, M., Jin, C., Ahmad, R., Zhang, Y., Kui, L., Li, W., Yasumizu, Y., Hong, D., Miyo, M., Hiraki, M., Maeda, T., Suzuki, Y., Takahashi, H., Samur, M., & Kufe, D. (2019). Targeting MUC1-C inhibits TWIST1 signaling in triple-negative breast cancer. Molecular Cancer Therapeutics, 18(10), 1744–1754. https://doi.org/10.1158/1535-7163.Mct-19-0156.CrossRefPubMedPubMedCentral

73.

Rajabi, H., Alam, M., Takahashi, H., Kharbanda, A., Guha, M., Ahmad, R., & Kufe, D. (2014). MUC1-C oncoprotein activates the ZEB1/miR-200c regulatory loop and epithelial-mesenchymal transition. Oncogene, 33(13), 1680–1689. https://doi.org/10.1038/onc.2013.114.CrossRefPubMed

74.

Grover, P., Nath, S., Nye, M. D., Zhou, R., Ahmad, M., & Mukherjee, P. (2018). SMAD4-independent activation of TGF-β signaling by MUC1 in a human pancreatic cancer cell line. Oncotarget, 9(6), 6897–6910. https://doi.org/10.18632/oncotarget.23966.CrossRefPubMedPubMedCentral

75.

Rachagani, S., Macha, M. A., Ponnusamy, M. P., Haridas, D., Kaur, S., Jain, M., & Batra, S. K. (2012). MUC4 potentiates invasion and metastasis of pancreatic cancer cells through stabilization of fibroblast growth factor receptor 1. Carcinogenesis, 33(10), 1953–1964. https://doi.org/10.1093/carcin/bgs225.CrossRefPubMedPubMedCentral

76.

Muniyan, S., Haridas, D., Chugh, S., Rachagani, S., Lakshmanan, I., Gupta, S., Seshacharyulu, P., Smith, L. M., Ponnusamy, M. P., & Batra S. K. (2016). MUC16 contributes to the metastasis of pancreatic ductal adenocarcinoma through focal adhesion mediated signaling mechanism. Genes & Cancer, 7(3–4), 110–124. https://doi.org/10.18632/genesandcancer.104.

77.

Hanahan, D., & Weinberg, R. A. (2011). Hallmarks of cancer: The next generation. Cell, 144(5), 646–674. https://doi.org/10.1016/j.cell.2011.02.013.CrossRef

78.

Frezza, C. (2020). Metabolism and cancer: The future is now. British Journal of Cancer, 122(2), 133–135. https://doi.org/10.1038/s41416-019-0667-3.CrossRefPubMed

79.

Jung, J. G., & Le, A. (2018). Targeting metabolic cross talk between cancer cells and cancer-associated fibroblasts. Advances in Experimental Medicine and Biology, 1063, 167–178. https://doi.org/10.1007/978-3-319-77736-8_12.CrossRefPubMed

80.

Chaika, N. V., Gebregiworgis, T., Lewallen, M. E., Purohit, V., Radhakrishnan, P., Liu, X., Zhang, B., Mehla, K., Brown, R. B., Caffrey, T., Yu, F., Johnson, K. R., Powers, R., Hollingsworth, M. A., & Singh, P. K. (2012). MUC1 mucin stabilizes and activates hypoxia-inducible factor 1 alpha to regulate metabolism in pancreatic cancer. Proceedings of the National Academy of Sciences of the United States of America, 109(34), 13787–13792. https://doi.org/10.1073/pnas.1203339109.CrossRefPubMedPubMedCentral

81.

Kosugi, M., Ahmad, R., Alam, M., Uchida, Y., & Kufe, D. (2011). MUC1-C oncoprotein regulates glycolysis and pyruvate kinase M2 activity in cancer cells. PLoS One, 6(11), e28234. https://doi.org/10.1371/journal.pone.0028234.CrossRefPubMedPubMedCentral

82.

Raina, D., Kharbanda, S., & Kufe, D. (2004). The MUC1 oncoprotein activates the anti-apoptotic phosphoinositide 3-kinase/Akt and Bcl-xL pathways in rat 3Y1 fibroblasts. The Journal of Biological Chemistry, 279(20), 20607–20612. https://doi.org/10.1074/jbc.M310538200.CrossRefPubMed

83.

Mehla, K., & Singh, P. K. (2014). MUC1: A novel metabolic master regulator. Biochimica et Biophysica Acta, 1845(2), 126–135. https://doi.org/10.1016/j.bbcan.2014.01.001.CrossRefPubMedPubMedCentral

84.

Yoshida, K., & Miki, Y. (2004). Role of BRCA1 and BRCA2 as regulators of DNA repair, transcription, and cell cycle in response to DNA damage. Cancer Science, 95(11), 866–871. https://doi.org/10.1111/j.1349-7006.2004.tb02195.x.CrossRefPubMed

85.

Gunda, V., Souchek, J., Abrego, J., Shukla, S. K., Goode, G. D., Vernucci, E., Dasgupta, A., Chaika, N. V., King, R. J., Li, S., Wang, S., Yu, F., Bessho, T., Lin, C., & Singh, P. K. (2017). MUC1-mediated metabolic alterations regulate response to radiotherapy in pancreatic cancer. Clinical Cancer Research, 23(19), 5881–5891. https://doi.org/10.1158/1078-0432.Ccr-17-1151.CrossRefPubMedPubMedCentral

86.

Chiyoda, T., Hart, P. C., Eckert, M. A., McGregor, S. M., Lastra, R. R., Hamamoto, R., Nakamura, Y., Yamada, S. D., Olopade, O. I., Lengyel, E., & Romero, I. L. (2017). Loss of BRCA1 in the cells of origin of ovarian cancer induces glycolysis: A window of opportunity for ovarian cancer Chemoprevention. Cancer Prevention Research (Philadelphia, Pa.), 10(4), 255–266. https://doi.org/10.1158/1940-6207.Capr-16-0281.CrossRef

87.

Fu, X., Tang, N., Xie, W. Q., Mao, L., & Qiu, Y. D. (2020). MUC1 promotes glycolysis through inhibiting BRCA1 expression in pancreatic cancer. Chinese Journal of Natural Medicines, 18(3), 178–185. https://doi.org/10.1016/s1875-5364(20)30019-4.CrossRefPubMed

88.

Leng, Y., Cao, C., Ren, J., Huang, L., Chen, D., Ito, M., & Kufe, D. (2007). Nuclear import of the MUC1-C oncoprotein is mediated by nucleoporin Nup62. The Journal of Biological Chemistry, 282(27), 19321–19330. https://doi.org/10.1074/jbc.M703222200.CrossRefPubMed

89.

Raina, D., Ahmad, R., Rajabi, H., Panchamoorthy, G., Kharbanda, S., & Kufe, D. (2012). Targeting cysteine-mediated dimerization of the MUC1-C oncoprotein in human cancer cells. International Journal of Oncology, 40(5), 1643–1649. https://doi.org/10.3892/ijo.2011.1308.CrossRefPubMed

90.

Raina, D., Kosugi, M., Ahmad, R., Panchamoorthy, G., Rajabi, H., Alam, M., Shimamura, T., Shapiro, G. I., Supko, J., Kharbanda, S., & Kufe, D. (2011). Dependence on the MUC1-C oncoprotein in non-small cell lung cancer cells. Molecular Cancer Therapeutics, 10(5), 806–816. https://doi.org/10.1158/1535-7163.Mct-10-1050.CrossRefPubMedPubMedCentral

91.

GongSun, X., Zhao, Y., Jiang, B., Xin, Z., Shi, M., Song, L., Qin, Q. M., Wang, Q., & Liu, X. Y. (2019). Inhibition of MUC1-C regulates metabolism by AKT pathway in esophageal squamous cell carcinoma. Journal of Cellular Physiology, 234(7), 12019–12028. https://doi.org/10.1002/jcp.27863.CrossRefPubMed

92.

Kumari, S., Khan, S., Gupta, S. C., Kashyap, V. K., Yallapu, M. M., Chauhan, S. C., & Jaggi, M. (2018). MUC13 contributes to rewiring of glucose metabolism in pancreatic cancer. Oncogenesis, 7(2), 19. https://doi.org/10.1038/s41389-018-0031-0.CrossRefPubMedPubMedCentral

93.

Haridas, D., Chakraborty, S., Ponnusamy, M. P., Lakshmanan, I., Rachagani, S., Cruz, E., Kumar, S., Das, S., Lele, S. M., Anderson, J. M., Wittel, U. A., Hollingsworth, M. A., & Batra, S. K. (2011). Pathobiological implications of MUC16 expression in pancreatic cancer. PLoS One, 6(10), e26839. https://doi.org/10.1371/journal.pone.0026839.CrossRefPubMedPubMedCentral

94.

Shukla, S. K., Gunda, V., Abrego, J., Haridas, D., Mishra, A., Souchek, J., Chaika, N. V., Yu, F., Sasson, A. R., Lazenby, A. J., Batra, S. K., & Singh, P. K. (2015). MUC16-mediated activation of mTOR and c-Myc reprograms pancreatic cancer metabolism. Oncotarget, 6(22), 19118–19131. https://doi.org/10.18632/oncotarget.4078.

95.

Shimobayashi, M., & Hall, M. N. (2014). Making new contacts: The mTOR network in metabolism and signalling crosstalk. Nature Reviews. Molecular Cell Biology, 15(3), 155–162. https://doi.org/10.1038/nrm3757.CrossRefPubMed

96.

Düvel, K., Yecies, J. L., Menon, S., Raman, P., Lipovsky, A. I., Souza, A. L., Triantafellow, E., Ma, Q., Gorski, R., Cleaver, S., Vander Heiden, M. G., MacKeigan, J. P., Finan, P. M., Clish, C. B., Murphy, L. O., & Manning, B. D. (2010). Activation of a metabolic gene regulatory network downstream of mTOR complex 1. Molecular Cell, 39(2), 171–183. https://doi.org/10.1016/j.molcel.2010.06.022.CrossRefPubMedPubMedCentral

97.

Nomura, D. K., & Cravatt, B. F. (2013). Lipid metabolism in cancer. Biochimica et Biophysica Acta, 1831(10), 1497–1498. https://doi.org/10.1016/j.bbalip.2013.08.001.CrossRefPubMed

98.

Mashima, T., Seimiya, H., & Tsuruo, T. (2009). De novo fatty-acid synthesis and related pathways as molecular targets for cancer therapy. British Journal of Cancer, 100(9), 1369–1372. https://doi.org/10.1038/sj.bjc.6605007.CrossRefPubMedPubMedCentral

99.

Liu, Y. (2006). Fatty acid oxidation is a dominant bioenergetic pathway in prostate cancer. Prostate Cancer and Prostatic Diseases, 9(3), 230–234. https://doi.org/10.1038/sj.pcan.4500879.CrossRefPubMed

100.

Mukherjee, A., Wu, J., Barbour, S., & Fang, X. (2012). Lysophosphatidic acid activates lipogenic pathways and de novo lipid synthesis in ovarian cancer cells. The Journal of Biological Chemistry, 287(30), 24990–25000. https://doi.org/10.1074/jbc.M112.340083.CrossRefPubMedPubMedCentral

101.

Martel, P. M., Bingham, C. M., McGraw, C. J., Baker, C. L., Morganelli, P. M., Meng, M. L., Armstrong, J. M., Moncur, J. T., & Kinlaw, W. B., (2006). S14 protein in breast cancer cells: Direct evidence of regulation by SREBP-1c, superinduction with progestin, and effects on cell growth. Experimental Cell Research, 312(3), 278–288. https://doi.org/10.1016/j.yexcr.2005.10.022.

102.

Migita, T., Narita, T., Nomura, K., Miyagi, E., Inazuka, F., Matsuura, M., Ushijima, M., Mashima, T., Seimiya, H., Satoh, Y., Okumura, S., Nakagawa, K., & Ishikawa, Y. (2008). ATP citrate lyase: Activation and therapeutic implications in non-small cell lung cancer. Cancer Research, 68(20), 8547–8554. https://doi.org/10.1158/0008-5472.Can-08-1235.CrossRefPubMed

103.

Menendez, J. A., & Lupu, R. (2007). Fatty acid synthase and the lipogenic phenotype in cancer pathogenesis. Nature Reviews. Cancer, 7(10), 763–777. https://doi.org/10.1038/nrc2222.CrossRefPubMed

104.

Furuta, E., Pai, S. K., Zhan, R., Bandyopadhyay, S., Watabe, M., Mo, Y. Y., Hirota, S., Hosobe, S., Tsukada, T., Miura, K., Kamada, S., Saito, K., Iiizumi, M., Liu, W., Ericsson, J., & Watabe, K. (2008). Fatty acid synthase gene is upregulated by hypoxia via activation of Akt and sterol regulatory element binding protein-1. Cancer Research, 68(4), 1003–1011. https://doi.org/10.1158/0008-5472.Can-07-2489.CrossRefPubMed

105.

Taylor-Papadimitriou, J., Burchell, J. M., Graham, R., & Beatson, R. (2018). Latest developments in MUC1 immunotherapy. Biochemical Society Transactions, 46(3), 659–668. https://doi.org/10.1042/bst20170400.CrossRefPubMedPubMedCentral

106.

Panchamoorthy, G., Jin, C., Raina, D., Bharti, A., Yamamoto, M., Adeebge, D., Zhao, Q., Bronson, R., Jiang, S., Li, L., Suzuki, Y., Tagde, A., Ghoroghchian, P. P., Wong, K. K., Kharbanda, S., & Kufe, D. (2018). Targeting the human MUC1-C oncoprotein with an antibody-drug conjugate. JCI Insight, 3(12). https://doi.org/10.1172/jci.insight.99880.

107.

Liberelle, M., Magnez, R., Thuru, X., Bencheikh, Y., Ravez, S., Quenon, C., Drucbert, A. S., Foulon, C., Melnyk, P., van Seuningen, I., & Lebègue, N. (2019). MUC4-ErbB2 oncogenic complex: Binding studies using microscale thermophoresis. Scientific Reports, 9(1), 16678. https://doi.org/10.1038/s41598-019-53099-0.CrossRefPubMedPubMedCentral

108.

Das, S., & Batra, S. K. (2015). Understanding the unique attributes of MUC16 (CA125): Potential implications in targeted therapy. Cancer Research, 75(22), 4669–4674. https://doi.org/10.1158/0008-5472.Can-15-1050.CrossRefPubMedPubMedCentral

109.

Aithal, A., Rauth, S., Kshirsagar, P., Shah, A., Lakshmanan, I., Junker, W. M., Jain, M., Ponnusamy, M. P., & Batra, S. K. (2018). MUC16 as a novel target for cancer therapy. Expert Opinion on Therapeutic Targets, 22(8), 675–686. https://doi.org/10.1080/14728222.2018.1498845.CrossRefPubMedPubMedCentral

110.

Patel, S. P., Bristol, A., Saric, O., Wang, X. P., Dubeykovskiy, A., Arlen, P. M., & Morse, M. A. (2013). Anti-tumor activity of a novel monoclonal antibody, NPC-1C, optimized for recognition of tumor antigen MUC5AC variant in preclinical models. Cancer Immunology, Immunotherapy, 62(6), 1011–1019. https://doi.org/10.1007/s00262-013-1420-z.CrossRefPubMed

Titel: Mucins reprogram stemness, metabolism and promote chemoresistance during cancer progression
verfasst von: Saravanakumar Marimuthu
Sanchita Rauth
Koelina Ganguly
Chunmeng Zhang
Imayavaramban Lakshmanan
Surinder K. Batra
Moorthy P. Ponnusamy
Publikationsdatum: 04.04.2021
Verlag: Springer US
Erschienen in: Cancer and Metastasis Reviews / Ausgabe 2/2021
Print ISSN: 0167-7659
Elektronische ISSN: 1573-7233
DOI: https://doi.org/10.1007/s10555-021-09959-1

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Mucins reprogram stemness, metabolism and promote chemoresistance during cancer progression

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