Abstract
Macroautophagy (herein termed autophagy) is evolutionarily highly conserved across eukaryotic cells and represents an intracellular catabolic process that targets damaged macromolecules and organelles for degradation. Autophagy is dysregulated in various human diseases including cancer. In addition, many drugs currently used for the treatment of cancer can engage autophagy, which typically promotes cancer cell survival by mitigating cellular stress. However, under certain circumstances activation of autophagy upon anticancer drug treatment can also trigger a lethal type of autophagy termed autophagic cell death (ACD). This may pave new avenues for exploiting the autophagic circuitry in oncology. This review presents the concept and some examples of anticancer drug-induced ACD.
Acknowledgments
The expert secretarial assistance of C. Hugenberg is greatly appreciated.
Funding: This work has been partly supported by grants from the DFG SFB 1177 and BMBF (to S.F.).
Conflict of interest statement: The author declares that she has no conflict of interest.
References
Armstrong, J.L., Hill, D.S., McKee, C.S., Hernandez-Tiedra, S., Lorente, M., Lopez-Valero, I., Eleni Anagnostou, M., Babatunde, F., Corazzari, M., Redfern, C.P.F., et al. (2015). Exploiting cannabinoid-induced cytotoxic autophagy to drive melanoma cell death. J. Invest. Dermatol. 135, 1629–1637.10.1038/jid.2015.45Search in Google Scholar PubMed
Balakrishnan, K., Wierda, W.G., Keating, M.J., and Gandhi, V. (2008). Gossypol, a BH3 mimetic, induces apoptosis in chronic lymphocytic leukemia cells. Blood 112, 1971–1980.10.1182/blood-2007-12-126946Search in Google Scholar PubMed PubMed Central
Basit, F., Cristofanon, S., and Fulda, S. (2013). Obatoclax (GX15-070) triggers necroptosis by promoting the assembly of the necrosome on autophagosomal membranes. Cell Death Differ. 20, 1161–1173.10.1038/cdd.2013.45Search in Google Scholar PubMed PubMed Central
Bonapace, L., Bornhauser, B.C., Schmitz, M., Cario, G., Ziegler, U., Niggli, F.K., Schafer, B.W., Schrappe, M., Stanulla, M., and Bourquin, J.P. (2010). Induction of autophagy-dependent necroptosis is required for childhood acute lymphoblastic leukemia cells to overcome glucocorticoid resistance. J. Clin. Invest. 120, 1310–1323.10.1172/JCI39987Search in Google Scholar PubMed PubMed Central
Brem, E.A., Thudium, K., Khubchandani, S., Tsai, P.C., Olejniczak, S.H., Bhat, S., Riaz, W., Gu, J., Iqbal, A., Campagna, R., et al. (2011). Distinct cellular and therapeutic effects of obatoclax in rituximab-sensitive and -resistant lymphomas. Br. J. Haematol. 153, 599–611.10.1111/j.1365-2141.2011.08669.xSearch in Google Scholar PubMed PubMed Central
Cao, Q., Yu, C., Xue, R., Hsueh, W., Pan, P., Chen, Z., Wang, S., McNutt, M., and Gu, J. (2008). Autophagy induced by suberoylanilide hydroxamic acid in Hela S3 cells involves inhibition of protein kinase B and up-regulation of Beclin 1. Int. J. Biochem. Cell Biol. 40, 272–283.10.1016/j.biocel.2007.07.020Search in Google Scholar PubMed
Codogno, P. and Meijer, A.J. (2005). Autophagy and signaling: their role in cell survival and cell death. Cell Death Differ. 12, 1509–1518.10.1038/sj.cdd.4401751Search in Google Scholar PubMed
Fulda, S. and Kogel, D. (2015). Cell death by autophagy: emerging molecular mechanisms and implications for cancer therapy. Oncogene 34, 5105–5113.10.1038/onc.2014.458Search in Google Scholar PubMed
Galluzzi, L., Bravo-San Pedro, J.M., Vitale, I., Aaronson, S.A., Abrams, J.M., Adam, D., Alnemri, E.S., Altucci, L., Andrews, D., Annicchiarico-Petruzzelli, M., et al. (2015). Essential versus accessory aspects of cell death: recommendations of the NCCD 2015. Cell Death Differ. 22, 58–73.10.1038/cdd.2014.137Search in Google Scholar PubMed PubMed Central
Galluzzi, L., Baehrecke, E.H., Ballabio, A., Boya, P., Bravo-San Pedro, J.M., Cecconi, F., Choi, A.M., Chu, C.T., Codogno, P., Colombo, M.I., et al. (2017). Molecular definitions of autophagy and related processes. EMBO J. 36, 1811–1836.10.15252/embj.201796697Search in Google Scholar PubMed PubMed Central
Gozuacik, D. and Kimchi, A. (2004). Autophagy as a cell death and tumor suppressor mechanism. Oncogene 23, 2891–2906.10.1038/sj.onc.1207521Search in Google Scholar PubMed
He, C. and Klionsky, D.J. (2009). Regulation mechanisms and signaling pathways of autophagy. Annu. Rev. Genet. 43, 67–93.10.1146/annurev-genet-102808-114910Search in Google Scholar PubMed PubMed Central
Heidari, N., Hicks, M.A., and Harada, H. (2010). GX15-070 (obatoclax) overcomes glucocorticoid resistance in acute lymphoblastic leukemia through induction of apoptosis and autophagy. Cell Death Dis. 1, e76.10.1038/cddis.2010.53Search in Google Scholar PubMed PubMed Central
Hernandez-Tiedra, S., Fabrias, G., Davila, D., Salanueva, I.J., Casas, J., Montes, L.R., Anton, Z., Garcia-Taboada, E., Salazar-Roa, M., Lorente, M., et al. (2016). Dihydroceramide accumulation mediates cytotoxic autophagy of cancer cells via autolysosome destabilization. Autophagy 12, 2213–2229.10.1080/15548627.2016.1213927Search in Google Scholar PubMed PubMed Central
Joudeh, J. and Claxton, D. (2012). Obatoclax mesylate: pharmacology and potential for therapy of hematological neoplasms. Expert Opin. Investig. Drugs 21, 363–373.10.1517/13543784.2012.652302Search in Google Scholar PubMed
Lian, J., Wu, X., He, F., Karnak, D., Tang, W., Meng, Y., Xiang, D., Ji, M., Lawrence, T.S., and Xu, L. (2011). A natural BH3 mimetic induces autophagy in apoptosis-resistant prostate cancer via modulating Bcl-2-Beclin1 interaction at endoplasmic reticulum. Cell Death Differ. 18, 60–71.10.1038/cdd.2010.74Search in Google Scholar PubMed PubMed Central
Lindqvist, L.M. and Vaux, D.L. (2014). BCL2 and related prosurvival proteins require BAK1 and BAX to affect autophagy. Autophagy 10, 1474–1475.10.4161/auto.29639Search in Google Scholar PubMed PubMed Central
Lindqvist, L.M., Heinlein, M., Huang, D.C., and Vaux, D.L. (2014). Prosurvival Bcl-2 family members affect autophagy only indirectly, by inhibiting Bax and Bak. Proc. Natl. Acad. Sci. USA 111, 8512–8517.10.1073/pnas.1406425111Search in Google Scholar PubMed PubMed Central
Liu, Y.L., Yang, P.M., Shun, C.T., Wu, M.S., Weng, J.R., and Chen, C.C. (2010). Autophagy potentiates the anti-cancer effects of the histone deacetylase inhibitors in hepatocellular carcinoma. Autophagy 6, 1057–1065.10.4161/auto.6.8.13365Search in Google Scholar PubMed
Maiuri, M.C., Le Toumelin, G., Criollo, A., Rain, J.C., Gautier, F., Juin, P., Tasdemir, E., Pierron, G., Troulinaki, K., Tavernarakis, N., et al. (2007). Functional and physical interaction between Bcl-X(L) and a BH3-like domain in Beclin-1. EMBO J. 26, 2527–2539.10.1038/sj.emboj.7601689Search in Google Scholar PubMed PubMed Central
Meng, Y., Tang, W., Dai, Y., Wu, X., Liu, M., Ji, Q., Ji, M., Pienta, K., Lawrence, T., and Xu, L. (2008). Natural BH3 mimetic (−)-gossypol chemosensitizes human prostate cancer via Bcl-xL inhibition accompanied by increase of Puma and Noxa. Mol. Cancer Ther. 7, 2192–2202.10.1158/1535-7163.MCT-08-0333Search in Google Scholar PubMed PubMed Central
Nguyen, M., Marcellus, R.C., Roulston, A., Watson, M., Serfass, L., Murthy Madiraju, S.R., Goulet, D., Viallet, J., Belec, L, Billot, X., et al. (2007). Small molecule obatoclax (GX15-070) antagonizes MCL-1 and overcomes MCL-1-mediated resistance to apoptosis. Proc. Natl. Acad. Sci. USA 104, 19512–19517.10.1073/pnas.0709443104Search in Google Scholar PubMed PubMed Central
Paoluzzi, L., Gonen, M., Gardner, J.R., Mastrella, J., Yang, D., Holmlund, J., Sorensen, M., Leopold, L., Manova, K., Marcucci, G., et al. (2008). Targeting Bcl-2 family members with the BH3 mimetic AT-101 markedly enhances the therapeutic effects of chemotherapeutic agents in in vitro and in vivo models of B-cell lymphoma. Blood 111, 5350–5358.10.1182/blood-2007-12-129833Search in Google Scholar PubMed
Pattingre, S. and Levine, B. (2006). Bcl-2 inhibition of autophagy: a new route to cancer? Cancer Res. 66, 2885–2888.10.1158/0008-5472.CAN-05-4412Search in Google Scholar PubMed
Pattingre, S., Tassa, A., Qu, X., Garuti, R., Liang, X.H., Mizushima, N., Packer, M., Schneider, M.D., and Levine, B. (2005). Bcl-2 antiapoptotic proteins inhibit Beclin 1-dependent autophagy. Cell 122, 927–939.10.1016/j.cell.2005.07.002Search in Google Scholar PubMed
Salazar, M., Carracedo, A., Salanueva, I.J., Hernandez-Tiedra, S., Lorente, M., Egia, A., Vazquez, P., Blazquez, C., Torres, S., Garcia, S., et al. (2009). Cannabinoid action induces autophagy-mediated cell death through stimulation of ER stress in human glioma cells. J. Clin. Invest. 119, 1359–1372.10.1172/JCI37948Search in Google Scholar
Shchors, K., Massaras, A., and Hanahan, D. (2015). Dual targeting of the autophagic regulatory circuitry in gliomas with repurposed drugs elicits cell-lethal autophagy and therapeutic benefit. Cancer Cell 28, 456–471.10.1016/j.ccell.2015.08.012Search in Google Scholar PubMed
Shen, S., Kepp, O., Michaud, M., Martins, I., Minoux, H., Metivier, D., Maiuri, M.C., Kroemer, R.T., and Kroemer, G. (2011). Association and dissociation of autophagy, apoptosis and necrosis by systematic chemical study. Oncogene 30, 4544–4556.10.1038/onc.2011.168Search in Google Scholar PubMed
Tang, Z., Takahashi, Y., Chen, C., Liu, Y., He, H., Tsotakos, N., Serfass, J.M., Gebru, M.T., Chen, H., Young, M.M., et al. (2017). Atg2A/B deficiency switches cytoprotective autophagy to non-canonical caspase-8 activation and apoptosis. Cell Death Differ. 24, 2127–2138.10.1038/cdd.2017.133Search in Google Scholar PubMed PubMed Central
Vara, D., Salazar, M., Olea-Herrero, N., Guzman, M., Velasco, G., and Diaz-Laviada, I. (2011). Anti-tumoral action of cannabinoids on hepatocellular carcinoma: role of AMPK-dependent activation of autophagy. Cell Death Differ. 18, 1099–1111.10.1038/cdd.2011.32Search in Google Scholar PubMed PubMed Central
Voss, V., Senft, C., Lang, V., Ronellenfitsch, M.W., Steinbach, J.P., Seifert, V., and Kögel, D. (2010). The pan-bcl-2 inhibitor (−)-gossypol triggers autophagic cell death in malignant glioma. Mol. Cancer Res. 8, 1002–1016.10.1158/1541-7786.MCR-09-0562Search in Google Scholar PubMed
Wolter, K.G., Wang, S.J., Henson, B.S., Wang, S., Griffith, K.A., Kumar, B., Chen, J., Carey, T.E., Bradford, C.R., and D’Silva, N.J. (2006). (−)-Gossypol inhibits growth and promotes apoptosis of human head and neck squamous cell carcinoma in vivo. Neoplasia 8, 163–172.10.1593/neo.05691Search in Google Scholar PubMed PubMed Central
Yamamoto, S., Tanaka, K., Sakimura, R., Okada, T., Nakamura, T., Li, Y., Takasaki, M., Nakabeppu, Y., and Iwamoto, Y. (2008). Suberoylanilide hydroxamic acid (SAHA) induces apoptosis or autophagy-associated cell death in chondrosarcoma cell lines. Anticancer Res. 28, 1585–1591.Search in Google Scholar
Young, M.M., Takahashi, Y., Khan, O., Park, S., Hori, T., Yun, J., Sharma, A.K., Amin, S., Hu, C.D., Zhang, J., et al. (2012). Autophagosomal membrane serves as platform for intracellular death-inducing signaling complex (iDISC)-mediated caspase-8 activation and apoptosis. J. Biol. Chem. 287, 12455–12468.10.1074/jbc.M111.309104Search in Google Scholar PubMed PubMed Central
Yu, L., Chen, Y., and Tooze, S.A. (2017). Autophagy pathway: cellular and molecular mechanisms. Autophagy 1–9.10.1080/15548627.2017.1378838Search in Google Scholar PubMed PubMed Central
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