Generic placeholder image

Anti-Cancer Agents in Medicinal Chemistry


ISSN (Print): 1871-5206
ISSN (Online): 1875-5992

Research Article

Selective Inhibition of Esophageal Cancer Stem-like Cells with Salinomycin

Author(s): Mahdi Zarei, Marie S. Jazi*, Mahboubeh Tajaldini, Ayyoob Khosravi and Jahanbakhsh Asadi

Volume 20, Issue 7, 2020

Page: [783 - 789] Pages: 7

DOI: 10.2174/1871520620666200310093125

Price: $65


Background: Targeting Cancer Stem-Like Cells (CSLCs) can provide promising new therapeutic strategies to inhibit cancer progression, metastasis and recurrence. Salinomycin (Sal), an antibacterial ionophore, has been shown to inhibit CSCs specifically. Recently, it has been reported that Sal can destabilize TAZ, the hypo pathway transducer in CSLCs.

Objectives: Here, in the current study, we aimed to assess the differential toxicity of Sal in esophageal CSLCs and its relation to TAZ gene expression.

Methods: The esophageal cancer cell line, KYSE-30, was used for the enrichment of CSLCs. The expression of TAZ was knocked down using specific siRNA transfection and then the cytotoxicity of Sal was measured using XTT assay. The qRT-PCR method was used for gene expression assessment and the sphere formation ability was monitored using light microscopy.

Results: Our findings showed that esophageal CSLCs over-express stemness-associated genes, including SOX2, OCT4 as well as TAZ (~14 fold, P value=0.02) transcription coactivator. We found Sal can selectively inhibit KYSE-30 CSLCs viability and sphere formation ability; however, TAZ knockdown does not change its differential toxicity.

Conclusion: Overall, our results indicated that Sal can selectively decrease the viability of esophageal CSLCs in a TAZ-independent manner.

Keywords: Salinomycin, esophageal cancer stem-like cell, selective toxicity, TAZ knockdown, CSLC, stemness.

Graphical Abstract
Napier, K.J.; Scheerer, M.; Misra, S. Esophageal cancer: A Review of epidemiology, pathogenesis, staging workup and treatment modalities. World J. Gastrointest. Oncol., 2014, 6(5), 112-120.
[] [PMID: 24834141]
Lou, F.; Sima, C.S.; Adusumilli, P.S.; Bains, M.S.; Sarkaria, I.S.; Rusch, V.W.; Rizk, N.P. Esophageal cancer recurrence patterns and implications for surveillance. J. Thorac. Oncol., 2013, 8(12), 1558-1562.
[] [PMID: 24389438]
Tan, B.T.; Park, C.Y.; Ailles, L.E.; Weissman, I.L. The cancer stem cell hypothesis: a work in progress. Lab. Invest., 2006, 86(12), 1203-1207.
[] [PMID: 17075578]
Zhi, Q.M.; Chen, X.H.; Ji, J.; Zhang, J.N.; Li, J.F.; Cai, Q.; Liu, B.Y.; Gu, Q.L.; Zhu, Z.G.; Yu, Y.Y. Salinomycin can effectively kill ALDH(high) stem-like cells on gastric cancer. Biomed. Pharmacother., 2011, 65(7), 509-515.
Mao, J.; Fan, S.; Ma, W.; Fan, P.; Wang, B.; Zhang, J.; Wang, H.; Tang, B.; Zhang, Q.; Yu, X.; Wang, L.; Song, B.; Li, L. Roles of Wnt/β-catenin signaling in the gastric cancer stem cells proliferation and salinomycin treatment. Cell Death Dis., 2014, 5(1), e1039-e1039.
[] [PMID: 24481453]
Ayob, A.Z.; Ramasamy, T.S. Cancer stem cells as key drivers of tumour progression. J. Biomed. Sci., 2018, 25(1), 20.
[] [PMID: 29506506]
Shimokawa, M.; Ohta, Y.; Nishikori, S.; Matano, M.; Takano, A.; Fujii, M.; Date, S.; Sugimoto, S.; Kanai, T.; Sato, T. Visualization and targeting of LGR5+ human colon cancer stem cells. Nature, 2017, 545(7653), 187-192.
[] [PMID: 28355176]
Batlle, E.; Clevers, H. Cancer stem cells revisited. Nat. Med., 2017, 23(10), 1124-1134.
[] [PMID: 28985214]
Korkaya, H.; Wicha, M.S. Selective targeting of cancer stem cells: A new concept in cancer therapeutics. BioDrugs Clin. Immunotherapeut.Biopharmaceut. Gene Ther.,, 2007, 21(5), 299-310.
Pan, D. The hippo signaling pathway in development and cancer. Dev. Cell, 2010, 19(4), 491-505.
[] [PMID: 20951342]
Zhao, B.; Li, L.; Wang, L.; Wang, C.Y.; Yu, J.; Guan, K.L. Cell detachment activates the Hippo pathway via cytoskeleton reorganization to induce anoikis. Genes Dev., 2012, 26(1), 54-68.
[] [PMID: 22215811]
Park, J.H.; Shin, J.E.; Park, H.W. The role of hippo pathway in cancer stem cell biology. Mol. Cells, 2018, 41(2), 83-92.
[PMID: 29429151]
Zanconato, F.; Cordenonsi, M.; Piccolo, S. YAP/TAZ at the roots of cancer. Cancer cell,, 2016, 29(6), 783-803.
[] [PMID: 10.1016/j.ccell.2016.05.005]
Cordenonsi, M.; Zanconato, F.; Azzolin, L.; Forcato, M.; Rosato, A.; Frasson, C.; Inui, M.; Montagner, M.; Parenti, A.R.; Poletti, A.; Daidone, M.G.; Dupont, S.; Basso, G.; Bicciato, S.; Piccolo, S. The Hippo transducer TAZ confers cancer stem cell-related traits on breast cancer cells. Cell, 2011, 147(4), 759-772.
[] [PMID: 22078877]
Muramatsu, T.; Imoto, I.; Matsui, T.; Kozaki, K.; Haruki, S.; Sudol, M.; Shimada, Y.; Tsuda, H.; Kawano, T.; Inazawa, J. YAP is a candidate oncogene for esophageal squamous cell carcinoma. Carcinogenesis, 2011, 32(3), 389-398.
[] [PMID: 21112960]
Song, S.; Ajani, J.A.; Honjo, S.; Maru, D.M.; Chen, Q.; Scott, A.W.; Heallen, T.R.; Xiao, L.; Hofstetter, W.L.; Weston, B.; Lee, J.H.; Wadhwa, R.; Sudo, K.; Stroehlein, J.R.; Martin, J.F.; Hung, M.C.; Johnson, R.L. Hippo coactivator YAP1 upregulates SOX9 and endows esophageal cancer cells with stem-like properties. Cancer Res., 2014, 74(15), 4170-4182.
[] [PMID: 24906622]
Gupta, P.B.; Onder, T.T.; Jiang, G.; Tao, K.; Kuperwasser, C.; Weinberg, R.A.; Lander, E.S. Identification of selective inhibitors of cancer stem cells by high-throughput screening. Cell, 2009, 138(4), 645-659.
[] [PMID: 19682730]
Fuchs, D.; Heinold, A.; Opelz, G.; Daniel, V.; Naujokat, C. Salinomycin induces apoptosis and overcomes apoptosis resistance in human cancer cells. Biochem. Biophys. Res. Commun., 2009, 390(3), 743-749.
[] [PMID: 19835841]
Kuo, S.Z.; Blair, K.J.; Rahimy, E.; Kiang, A.; Abhold, E.; Fan, J.B.; Wang-Rodriguez, J.; Altuna, X.; Ongkeko, W.M. Salinomycin induces cell death and differentiation in head and neck squamous cell carcinoma stem cells despite activation of epithelial-mesenchymal transition and Akt. BMC Cancer, 2012, 12, 556.
[] [PMID: 23176396]
Klose, J.; Eissele, J.; Volz, C.; Schmitt, S.; Ritter, A.; Ying, S.; Schmidt, T.; Heger, U.; Schneider, M.; Ulrich, A. Salinomycin inhibits metastatic colorectal cancer growth and interferes with Wnt/β-catenin signaling in CD133+ human colorectal cancer cells. BMC Cancer, 2016, 16(1), 896-896.
[] [PMID: 27855654]
Zhou, X.; Chadarevian, J.P.; Ruiz, B.; Ying, Q-L. Cytoplasmic and nuclear TAZ exert distinct functions in regulating primed pluripotency. Stem Cell Reports, 2017, 9(3), 732-741.
[] [PMID: 28844657]
Gargini, R.; Escoll, M.; García, E.; García-Escudero, R.; Wandosell, F.; Antón, I.M. WIP drives tumor progression through YAP/TAZ-dependent autonomous cell growth. Cell Rep., 2016, 17(8), 1962-1977.
[] [PMID: 27851961]
Harvey, K.F.; Zhang, X.; Thomas, D.M. The Hippo pathway and human cancer. Nat. Rev. Cancer, 2013, 13(4), 246-257.
[] [PMID: 23467301]
Yeo, M.K.; Kim, S.H.; Kim, J.M.; Huang, S.M.; Kim, M.R.; Song, K.S.; Kim, K.H. Correlation of expression of phosphorylated and non-phosphorylated Yes-associated protein with clinicopathological parameters in esophageal squamous cell carcinoma in a Korean population. Anticancer Res., 2012, 32(9), 3835-3840.
[PMID: 22993326]
Li, Z.; Wang, Y.; Zhu, Y.; Yuan, C.; Wang, D.; Zhang, W.; Qi, B.; Qiu, J.; Song, X.; Ye, J.; Wu, H.; Jiang, H.; Liu, L.; Zhang, Y.; Song, L.N.; Yang, J.; Cheng, J. The Hippo transducer TAZ promotes epithelial to mesenchymal transition and cancer stem cell maintenance in oral cancer. Mol. Oncol., 2015, 9(6), 1091-1105.
[] [PMID: 25704916]
Wang, Y. Effects of salinomycin on cancer stem cell in human lung adenocarcinoma A549 cells. Med. Chem., 2011, 7(2), 106-111.
[] [PMID: 21222617]
Zhi, Q.M.; Chen, X.H.; Ji, J.; Zhang, J.N.; Li, J.F.; Cai, Q.; Liu, B.Y.; Gu, Q.L.; Zhu, Z.G.; Yu, Y.Y. Salinomycin can effectively kill ALDH(high) stem-like cells on gastric cancer. Biomed. Pharmacother., 2011, 65(7), 509-515.
[] [PMID: 21996439]
Fuchs, D.; Daniel, V.; Sadeghi, M.; Opelz, G.; Naujokat, C. Salinomycin overcomes ABC transporter-mediated multidrug and apoptosis resistance in human leukemia stem cell-like KG-1a cells. Biochem. Biophys. Res. Commun., 2010, 394(4), 1098-1104.
[] [PMID: 20350531]
Mani, S.A.; Guo, W.; Liao, M.J.; Eaton, E.N.; Ayyanan, A.; Zhou, A.Y.; Brooks, M.; Reinhard, F.; Zhang, C.C.; Shipitsin, M.; Campbell, L.L.; Polyak, K.; Brisken, C.; Yang, J.; Weinberg, R.A. The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell, 2008, 133(4), 704-715.
[] [PMID: 18485877]
Zhou, Y.; Liang, C.; Xue, F.; Chen, W.; Zhi, X.; Feng, X.; Bai, X.; Liang, T. Salinomycin decreases doxorubicin resistance in hepatocellular carcinoma cells by inhibiting the β-catenin/TCF complex association via FOXO3a activation. Oncotarget, 2015, 6(12), 10350-10365.
[] [PMID: 25871400]
Li, R.; Dong, T.; Hu, C.; Lu, J.; Dai, J.; Liu, P. Salinomycin repressed the epithelial-mesenchymal transition of epithelial ovarian cancer cells via downregulating Wnt/β-catenin pathway. OncoTargets Ther., 2017, 10, 1317-1325.
[] [PMID: 28280366]
Lu, D.; Choi, M.Y.; Yu, J.; Castro, J.E.; Kipps, T.J.; Carson, D.A. Salinomycin inhibits Wnt signaling and selectively induces apoptosis in chronic lymphocytic leukemia cells. Proc. Natl. Acad. Sci. USA, 2011, 108(32), 13253-13257.
[] [PMID: 21788521]
Azzolin, L.; Zanconato, F.; Bresolin, S.; Forcato, M.; Basso, G.; Bicciato, S.; Cordenonsi, M.; Piccolo, S. Role of TAZ as mediator of Wnt signaling. Cell, 2012, 151(7), 1443-1456.
[] [PMID: 23245942]
Antoszczak, M.; Huczyński, A. Salinomycin and its derivatives - A new class of multiple-targeted “magic bullets”. Eur. J. Med. Chem., 2019, 176, 208-227.
[] [PMID: 31103901]

Rights & Permissions Print Export Cite as
© 2022 Bentham Science Publishers | Privacy Policy