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19.01.2018 | Original Article

LIMK/cofilin pathway and Slingshot are implicated in human colorectal cancer progression and chemoresistance

verfasst von: Helen Aggelou, Panagiota Chadla, Sofia Nikou, Sofia Karteri, Ioannis Maroulis, Haralabos P. Kalofonos, Helen Papadaki, Vasiliki Bravou

Erschienen in: Virchows Archiv | Ausgabe 5/2018

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Abstract

Cofilin phospho-regulation is important for actin filament turnover and is implicated in cancer. Phosphorylation of cofilin is mediated by LIM kinases (LIMKs) and dephosphorylation by Slingshot phosphatases (SSH). LIMKs and SSH promote cancer cell invasion and metastasis and represent novel anti-cancer targets. However, little is known regarding LIMK/cofilin and SSH in human colorectal cancer (CRC). In this study, we aimed to address their expression and significance in human CRC. We evaluated expression of non-phosphorylated (active) and phosphorylated cofilin, LIMK1, LIMK2, and SSH1 by immunohistochemistry in 143 human CRC samples in relation to clinicopathologic parameters, response of metastatic disease to chemotherapy, and epithelial-mesenchymal transition (EMT) markers β-catenin, E-cadherin, and ZEB. We show that active cofilin, LIMK1, LIMK2, and SSH1 are overexpressed in human CRC and are associated with tumor progression parameters. SSH1 is an independent predictor of lymph node metastasis by multivariate analysis. LIMK1 and SSH1 expression is also higher in non-responders to chemotherapy, and SSH1 is shown by multivariate analysis to independently predict response of metastatic disease to chemotherapy. Active cofilin, LIMK1, LIMK2, and SSH1 also correlated with the EMT markers examined. In addition, immunofluorescence analysis showed increased expression of active cofilin, LIMK1, LIMK2, and SSH1 in HT29 colon cancer cells resistant to 5-fluorouracil compared to parental HT29 cells. Our results suggest that F-actin regulators LIMK/cofilin pathway and SSH1 are associated with CRC progression and chemoresistance representing promising tumor biomarkers and therapeutic targets in CRC.

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Yamaguchi H, Condeelis J (2007) Regulation of the actin cytoskeleton in cancer cell migration and invasion. Biochim Biophys Acta 1773(5):642–652. https://doi.org/10.1016/j.bbamcr.2006.07.001 CrossRefPubMed

dos Remedios CG, Chhabra D, Kekic M, Dedova IV, Tsubakihara M, Berry DA, Nosworthy NJ (2003) Actin binding proteins: regulation of cytoskeletal microfilaments. Physiol Rev 83(2):433–473. https://doi.org/10.1152/physrev.00026.2002 CrossRefPubMed

Thiery JP (2002) Epithelial-mesenchymal transitions in tumour progression. Nat Rev Cancer 2(6):442–454. https://doi.org/10.1038/nrc822 CrossRefPubMed

Bamburg JR, Wiggan OP (2002) ADF/cofilin and actin dynamics in disease. Trends Cell Biol 12(12):598–605. https://doi.org/10.1016/S0962-8924(02)02404-2 CrossRefPubMed

Mizuno K (2013) Signaling mechanisms and functional roles of cofilin phosphorylation and dephosphorylation. Cell Signal 25(2):457–469. https://doi.org/10.1016/j.cellsig.2012.11.001 CrossRefPubMed

Shishkin S, Eremina L, Pashintseva N, Kovalev L, Kovaleva M (2016) Cofilin-1 and other ADF/Cofilin superfamily members in human malignant cells. Int J Mol Sci 18:10. https://doi.org/10.3390/ijms18010010 CrossRefPubMedCentral

Arber S, Barbayannis FA, Hanser H Schneider C, Stanyon CA, Bernard O, Caroni P (1998) Regulation of actin dynamics through phosphorylation of cofilin by LIM-kinase. Nature 393(6687):805–809. https://doi.org/10.1038/31729 CrossRefPubMed

Prunier C, Prudent R, Kapur R, Sadoul K, Lafanechère L (2017) LIM kinases: cofilin and beyond. Oncotarget 8:41749–41763. https://doi.org/10.18632/oncotarget.16978 CrossRefPubMedPubMedCentral

Niwa R, Nagata-Ohashi K, Takeichi M, Mizuno K, Uemura T (2002) Control of actin reorganization by Slingshot, a family of phosphatases that dephosphorylate ADF/cofilin. Cell 108:233–246CrossRefPubMed

10.

Huang TY, Der Mardirossian C, Bokoch GM (2006) Cofilin phosphatases and regulation of actin dynamics. Curr Opin Cell Biol 18(1):26–31. https://doi.org/10.1016/j.ceb.2005.11.005 CrossRefPubMed

11.

Nishita M, Tomizawa C, Yamamoto M, Horita Y, Ohashi K, Mizuno K (2002) Spatial and temporal regulation of cofilin activity by LIM kinase and Slingshot is critical for directional cell migration. J Cell Biol 171(2):349–359. https://doi.org/10.1083/jcb.200504029 CrossRef

12.

Horita Y, Ohashi K, Mukai M, Inoue M, Mizuno K (2008) Suppression of the invasive capacity of rat ascites hepatoma cells by knockdown of Slingshot or LIM kinase. J Biol Chem 283(10):6013–6021. https://doi.org/10.1074/jbc.M706538200 CrossRefPubMed

13.

Yoshioka K, Foletta V, Bernard O, Itoh K (2003) A role for LIM kinase in cancer invasion. Proc Natl Acad Sci U S A 100(12):7247–7252. https://doi.org/10.1073/pnas.1232344100 CrossRefPubMedPubMedCentral

14.

Davila M, Frost AR, Grizzle WE, Chakrabarti R (2003) LIM kinase 1 is essential for the invasive growth of prostate epithelial cells: implications in prostate cancer. J Biol Chem 278(38):36868–36875. https://doi.org/10.1074/jbc.M306196200 CrossRefPubMed

15.

Suyama E, Wadhwa R, Kawasaki H, Yaguchi T, Kaul SC, Nakajima M, Taira K (2004) LIM kinase-2 targeting as a possible anti-metastasis therapy. J Gene Med 6(3):357–363. https://doi.org/10.1002/jgm.491 CrossRefPubMed

16.

Vlecken DH, Bagowski CP (2009) LIMK1 and LIMK2 are important for metastatic behavior and tumor cell-induced angiogenesis of pancreatic cancer cells. Zebrafish 6(4):433–439. https://doi.org/10.1089/zeb.2009.0602 CrossRefPubMed

17.

McConnell BV, Koto K, Gutierrez-Hartmann A (2011) Nuclear and cytoplasmic LIMK1 enhances human breast cancer progression. Mol Cancer 10(1):75. https://doi.org/10.1186/1476-4598-10-75 CrossRefPubMedPubMedCentral

18.

Su J, Zhou Y, Pan Z, Shi L, Yang J, Liao A, Liao Q, Su Q (2017) Downregulation of LIMK1-ADF/cofilin by DADS inhibits the migration and invasion of colon cancer. Sci Rep 7:45624. https://doi.org/10.1038/srep45624 CrossRefPubMedPubMedCentral

19.

Lourenço FC, Munro J, Brown J, Cordero J, Stefanatos R, Strathdee K, Orange C, Feller SM, Sansom OJ, Vidal M, Murray GI, Olson MF (2014) Reduced LIMK2 expression in colorectal cancer reflects its role in limiting stem cell proliferation. Gut 63(3):480–493. https://doi.org/10.1136/gutjnl-2012-303883 CrossRefPubMed

20.

Wang Y, Kuramitsu Y, Kitagawa T, Baron B, Yoshino S, Maehara S, Maehara Y, Oka M, Nakamura K (2015) Cofilin-phosphatase slingshot-1L (SSH1L) is over-expressed in pancreatic cancer (PC) and contributes to tumor cell migration. Cancer Lett 360(2):171–176. https://doi.org/10.1016/j.canlet.2015.02.015 CrossRefPubMed

21.

Bravou V, Antonacopoulou A, Papanikolaou S, Nikou S, Lilis I, Giannopoulou E, Kalofonos HP (2015) Focal adhesion proteins α- and β-parvin are overexpressed in human colorectal cancer and correlate with tumor progression. Cancer Investig 33(8):387–397. https://doi.org/10.3109/07357907.2015.1047508 CrossRef

22.

Bravou V, Klironomos G, Papadaki E, Taraviras S, Varakis J (2006) ILK over-expression in human colon cancer progression correlates with activation of beta-catenin, down-regulation of E-cadherin and activation of the Akt-FKHR pathway. J Pathol 208(1):91–99. https://doi.org/10.1002/path.1860 CrossRefPubMed

23.

Amin MB, Edge S, Greene F, Byrd DR, Brookland RK, Washington MK, Gershenwald JE, Compton CC, Hess KR, Sullivan DC, Jessup JM, Brierley JD, Gaspar LE, Schilsky RL, Balch CM, Winchester DP, Asare E, Madera M, Gress DM, Meyer LR (2017) AJCC cancer staging manual, 8th edn. Springer, New York. https://doi.org/10.1007/978-3-319-40618-3 CrossRef

24.

Bosman FT, Carneiro F, Hruban RH, Theise ND (2010) World Health organization classification of tumours of the digestive system, 4th edn. IARC Press, Lyon

25.

Karavias D, Maroulis I, Papadaki H, Gogos C, Kakkos S, Karavias D, Bravou V (2016) Overexpression of CDT1 is a predictor of poor survival in patients with hepatocellular carcinoma. J Gastrointest Surg 20(3):568–579. https://doi.org/10.1007/s11605-015-2960-7 CrossRefPubMed

26.

Castro MA, Dal-Pizzol F, Zdanov S, Soares M, Müller CB, Lopes FM, Zanotto-Filho A, da Cruz Fernandes M, Moreira JC, Shacter E, Klamt F (2010) CFL1 expression levels as a prognostic and drug resistance marker in non small cell lung cancer. Cancer 116(15):3645–3655. https://doi.org/10.1002/cncr.25125 CrossRefPubMed

27.

Uhlén M, Fagerberg L, Hallström BM, Lindskog C, Oksvold P, Mardinoglu A, Sivertsson Å, Kampf C, Sjöstedt E, Asplund A, Olsson I, Edlund K, Lundberg E, Navani S, Szigyarto CA, Odeberg J, Djureinovic D, Takanen JO, Hober S, Alm T, Edqvist PH, Berling H, Tegel H, Mulder J, Rockberg J, Nilsson P, Schwenk JM, Hamsten M, von Feilitzen K, Forsberg M, Persson L, Johansson F, Zwahlen M, von Heijne G, Nielsen J, Pontén F (2015) Proteomics. Tissue-based map of the human proteome. Science 347(6220):1260419. https://doi.org/10.1126/science.1260419 CrossRefPubMed

28.

Coley HM (2004) Development of drug-resistant models. In: Langdom SP (ed) Cancer cell culture, methods and protocols. Humana Press Inc., Totowa, pp 267–273

29.

Cohen J (1969) Statistical power analysis for the behavioural sciences. Academic Press, New York

30.

Prudent R, Vassal-Stermann E, Nguyen CH, Pillet C, Martinez A, Prunier C, Barette C, Soleilhac E, Filhol O, Beghin A, Valdameri G, Honoré S, Aci-Sèche S, Grierson D, Antonipillai J, Li R, Di Pietro A, Dumontet C, Braguer D, Florent JC, Knapp S, Bernard O, Lafanechère L (2012) Pharmacological inhibition of LIM kinase stabilizes microtubules and inhibits neoplastic growth. Cancer Res 72(17):4429–4439. https://doi.org/10.1158/0008-5472.CAN-11-3342 CrossRefPubMed

31.

Prunier C, Josserand V, Vollaire J, Beerling E, Petropoulos C, Destaing O, Montemagno C, Hurbin A, Prudent R, de Koning L, Kapur R, Cohen PA, Albiges-Rizo C, Coll JL, van Rheenen J, Billaud M, Lafanechère L (2016) LIM kinase inhibitor Pyr1 reduces the growth and metastatic load of breast cancers. Cancer Res 76(12):3541–3552. https://doi.org/10.1158/0008-5472.CAN-15-1864 CrossRefPubMed

32.

Mardilovich K, Baugh M, Crighton D, Kowalczyk D, Gabrielsen M, Munro J, Croft DR, Lourenco F, James D, Kalna G, McGarry L, Rath O, Shanks E, Garnett MJ, McDermott U, Brookfield J, Charles M, Hammonds T, Olson MF (2015) LIM kinase inhibitors disrupt mitotic microtubule organization and impair tumor cell proliferation. Oncotarget 6(36):38469–38486. https://doi.org/10.18632/oncotarget.6288 CrossRefPubMedPubMedCentral

33.

Lee SY, Kim W, Lee YG, Kang HJ, Lee SH, Park SY, Min JK, Lee SR, Chung SJ (2017) Identification of sennoside A as a novel inhibitor of the slingshot (SSH) family proteins related to cancer metastasis. Pharmacol Res 119:422–430. https://doi.org/10.1016/j.phrs.2017.03.003 CrossRefPubMed

34.

Lu LI, Fu NI, Luo XU, Li XY, Li XP (2015) Overexpression of cofilin 1 in prostate cancer and the corresponding clinical implications. Oncol Lett 9(6):2757–2761. https://doi.org/10.3892/ol.2015.3133 CrossRefPubMedPubMedCentral

35.

Nishimura S, Tsuda H, Kataoka F, Arao T, Nomura H, Chiyoda T, Susumu N, Nishio K, Aoki D (2011) Overexpression of cofilin 1 can predict progression-free survival in patients with epithelial ovarian cancer receiving standard therapy. Hum Pathol 42(4):516–521. https://doi.org/10.1016/j.humpath.2010.07.019 CrossRefPubMed

36.

Peng XCL, Gong FM, Zhao YW, Zhou LX, Xie YW, Liao HL, Lin HJ, Li ZY, Tang MH, Tong AP (2011) Comparative proteomic approach identifies PKM2 and cofilin-1 as potential diagnostic, prognostic and therapeutic targets for pulmonary adenocarcinoma. PLoS One 6(11):e27309. https://doi.org/10.1371/journal.pone.0027309 CrossRefPubMedPubMedCentral

37.

Estornes Y, Gay F, Gevrey JC, Navoizat S, Nejjari M, Scoazec JY, Chayvialle JA, Saurin JC, Abello J (2007) Differential involvement of destrin and cofilin-1 in the control of invasive properties of Isreco1 human colon cancer cells. Int J Cancer 121(10):2162–2171. https://doi.org/10.1002/ijc.22911 CrossRefPubMed

38.

Nowak D, Mazur AJ, Popow-Woźniak A, Radwańska A, Mannherz HG, Malicka-Błaszkiewicz M (2010) Subcellular distribution and expression of cofilin and ezrin in human colon adenocarcinoma cell lines with different metastatic potential. Eur J Histochem 54:e14CrossRefPubMedPubMedCentral

39.

Popow-Woźniak A, Mazur AJ, Mannherz HG, Malicka-Błaszkiewicz M, Nowak D (2012) Cofilin overexpression affects actin cytoskeleton organization and migration of human colon adenocarcinoma cells. Histochem Cell Biol 138(5):725–736. https://doi.org/10.1007/s00418-012-0988-2 CrossRefPubMedPubMedCentral

40.

Davila M, Jhala D, Ghosh D, Grizzle WE, Chakrabarti R (2007) Expression of LIM kinase 1 is associated with reversible G1/S phase arrest, chromosomal instability and prostate cancer. Mol Cancer 6(1):40. https://doi.org/10.1186/1476-4598-6-40 CrossRefPubMedPubMedCentral

41.

Johnson EO, Chang KH, Ghosh S, Venkatesh C, Giger K, Low PS, Shah K (2012) LIMK2 is a crucial regulator and effector of Aurora-A-kinase-mediated malignancy. J Cell Sci 125(5):1204–1216. https://doi.org/10.1242/jcs.092304 CrossRefPubMed

42.

Chen C, Maimaiti Y, Zhijun S, Zeming L, Yawen G, Pan Y, Tao H (2017) Slingshot-1L, a cofilin phosphatase, induces primary breast cancer metastasis. Oncotarget 8:66195–66203. https://doi.org/10.18632/oncotarget.19855 PubMedPubMedCentralCrossRef

43.

Becker M, de Bastiani MA, Muller CB, Markoski MM, Castro MA, Klamt F (2014) High cofilin-1 levels correlate with cisplatin resistance in lung adenocarcinomas. Tumour Biol 35(2):1233–1238. https://doi.org/10.1007/s13277-013-1164-6 CrossRefPubMed

44.

Yan XDL, Pan LY, Yuan Y, Lang JH, Mao N (2007) Identification of platinum-resistance associated proteins through proteomic analysis of human ovarian cancer cells and their platinum-resistant sublines. J Proteome Res 6(2):772–780. https://doi.org/10.1021/pr060402r CrossRefPubMed

45.

Prunier C, Kapur R, Lafanechère L (2016) Targeting LIM kinases in taxane resistant tumors. Oncotarget 7(32):50816–50817. https://doi.org/10.18632/oncotarget.10816 CrossRefPubMedPubMedCentral

46.

Chen Q, Jiao D, Hu H, Song J, Yan J, Wu L, Xu LQ (2013) Downregulation of LIMK1 level inhibits migration of lung cancer cells and enhances sensitivity to chemotherapy drugs. Oncol Res 20(11):491–498. https://doi.org/10.3727/096504013X13657689382699 CrossRefPubMed

47.

Singh A, Settleman J (2010) EMT, cancer stem cells and drug resistance: an emerging axis of evil in the war on cancer. Oncogene 29(34):4741–4751. https://doi.org/10.1038/onc.2010.215 CrossRefPubMedPubMedCentral

48.

Shankar J, Nabi IR (2015) Correction: Actin cytoskeleton regulation of epithelial mesenchymal transition in metastatic cancer cells. PLoS One 10(7):e0132759. https://doi.org/10.1371/journal.pone.0132759 CrossRefPubMedPubMedCentral

49.

Haibo W, Lide T, Feng J, Hao G, Xiaojun D, Tengyang N, Jun F, Yanbing D, Weiming X, Yayun Q, Yanqing L (2017) Cofilin 1 induces the epithelial-mesenchymal transition of gastric cancer cells by promoting cytoskeletal rearrangement. Oncotarget. https://doi.org/10.18632/oncotarget.16608

50.

Su B, Su J, Zeng Y, Liu F, Xia H, Ma YH, Zhou ZG, Zhang S, Yang BM, Wu YH, Zeng X, Ai XH, Ling H, Jiang H, Su Q (2016) Diallyl disulfide suppresses epithelial-mesenchymal transition, invasion and proliferation by downregulation of LIMK1 in gastric cancer. Oncotarget 7(9):10498–10512. https://doi.org/10.18632/oncotarget.7252 PubMedPubMedCentralCrossRef

51.

Kim AY, Kwak JH, Je NK, Lee YH, Jung YS (2015) Epithelial-mesenchymal transition is associated with acquired resistance to 5-fluorocuracil in HT-29 colon cancer cells. Toxicol Res 31(2):151–156. https://doi.org/10.5487/TR.2015.31.2.151 CrossRefPubMedPubMedCentral

52.

Dallas NA, Xia L, Fan F, Gray MJ, Gaur P, van Buren G, Samuel S, Kim MP, Lim SJ, Ellis LM (2009) Chemoresistant colorectal cancer cells, the cancer stem cell phenotype, and increased sensitivity to insulin-like growth factor-I receptor inhibition. Cancer Res 69(5):1951–1957. https://doi.org/10.1158/0008-5472.CAN-08-2023 CrossRefPubMedPubMedCentral

Titel: LIMK/cofilin pathway and Slingshot are implicated in human colorectal cancer progression and chemoresistance
verfasst von: Helen Aggelou
Panagiota Chadla
Sofia Nikou
Sofia Karteri
Ioannis Maroulis
Haralabos P. Kalofonos
Helen Papadaki
Vasiliki Bravou
Publikationsdatum: 19.01.2018
Verlag: Springer Berlin Heidelberg
Erschienen in: Virchows Archiv / Ausgabe 5/2018
Print ISSN: 0945-6317
Elektronische ISSN: 1432-2307
DOI: https://doi.org/10.1007/s00428-018-2298-0

Neu im Fachgebiet Pathologie

01.04.2024 | Forensische Traumatologie | CME

Springer Medizin

LIMK/cofilin pathway and Slingshot are implicated in human colorectal cancer progression and chemoresistance

Abstract

Neu im Fachgebiet Pathologie

Theoretische Grundlagen von Explosionen und Explosionsverletzungen

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Springer Medizin

Abstract

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