Generic placeholder image

Current Pharmaceutical Biotechnology


ISSN (Print): 1389-2010
ISSN (Online): 1873-4316

Research Article

The Influence of Salinomycin on the Expression Profile of mRNAs Encoding Selected Caspases and MiRNAs Regulating their Expression in Endometrial Cancer Cell Line

Author(s): Krzysztof Januszyk*, Piotr Januszyk, Beniamin O. Grabarek, Dariusz Boroñ and Marcin Oplawski

Volume 21, Issue 14, 2020

Page: [1505 - 1515] Pages: 11

DOI: 10.2174/1389201021666200514095043

open access plus


Background: Apoptosis could take place in the pathway dependent on death receptors or pathways dependent on mitochondria. In both, a key role is played by enzymes with protease activity, known as caspases.

Aim: The aim of this study was to assess the variances in the expression pattern of caspase-dependent signaling pathways in the endometrial cancer cell line when treated with salinomycin. Additionally, the changes in the level of miRNA that potentially regulate these mRNAs were evaluated.

Materials and Methods: Endometrial cancer cells were treated with 1 μM of salinomycin for 12, 24 and 48 hours. Untreated cells made up the control culture. The molecular analysis consisted of screening mRNA and miRNA microarray expression profiles of caspases, and the evaluation of the expression of caspases 3,8 and 9 by RTqPCR, also on the protein level.

Results and Discussion: It was observed that 5 of the 14 differentiating mRNAs were commonly found for all incubation times of the cells and they corresponded with CASP3, CASP8, and CASP9 genes. The highest impact probability was determined between CASP3(up-regulated) and hsa- miR- 30d (FC -2.01), CASP8 (down-regulated) and hsa-miR-21 (FC +1.39) and between CASP9 (upregulated) and hsa-miR-1271 (FC +1.71).

Conclusion: Salinomycin induces the apoptosis of endometrial cancer cells. The largest increase in activity was noted for caspases 3 and 9, while the expression of caspase 8 was decreased. Salinomycin causes a regulatory effect on the transcriptomes of mRNA and miRNA in in vitro endometrial cancer cells.

Keywords: Mitochondria-dependent, independent apoptosis pathway, salinomycin, endometrial cancer, miRNA, mRNA, microarray expression.

Graphical Abstract
Julien, O.; Wells, J.A. Caspases and their substrates. Cell Death Differ., 2017, 24(8), 1380-1389.
[] [PMID: 28498362]
McArthur, K.; Kile, B.T. Apoptotic caspases: Multiple or mistaken identities? Trends Cell Biol., 2018, 28(6), 475-493.
[] [PMID: 29551258]
Poreba, M.; Groborz, K.; Navarro, M.; Snipas, S.J.; Drag, M.; Salvesen, G.S. Caspase selective reagents for diagnosing apoptotic mechanisms. Cell Death Differ., 2019, 26(2), 229-244.
[] [PMID: 29748600]
Kopeina, G.S.; Prokhorova, E.A.; Lavrik, I.N.; Zhivotovsky, B. Alterations in the nucleocytoplasmic transport in apoptosis: Caspases lead the way. Cell Prolif., 2018, 51(5)e12467
[] [PMID: 29947118]
Slattery, M.L.; Mullany, L.E.; Sakoda, L.C.; Wolff, R.K.; Samowitz, W.S.; Herrick, J.S. Dysregulated genes and miRNAs in the apoptosis pathway in colorectal cancer patients. Apoptosis, 2018, 23(3-4), 237-250.
[] [PMID: 29516317]
Anderson, G.R.; Wardell, S.E.; Cakir, M.; Yip, C.; Ahn, Y.R.; Ali, M.; Yllanes, A.P.; Chao, C.A.; McDonnell, D.P.; Wood, K.C. Dysregulation of mitochondrial dynamics proteins are a targetable feature of human tumors. Nat. Commun., 2018, 9(1), 1677.
[] [PMID: 29700304]
Chen, X.; Wang, L.; Qu, J.; Guan, N.N.; Li, J.Q. Predicting miRNA-disease association based on inductive matrix completion. Bioinformatics, 2018, 34(24), 4256-4265.
[] [PMID: 29939227]
Vannini, I.; Fanini, F.; Fabbri, M. Emerging roles of microRNAs in cancer. Curr. Opin. Genet. Dev., 2018, 48, 128-133.
[] [PMID: 29429825]
Stennicke, H.R.; Salvesen, G.S. Caspases - controlling intracellular signals by protease zymogen activation. Biochim. Biophys. Acta, 2000, 1477(1-2), 299-306.
[ ] [PMID: 10708865]
Man, S.M.; Kanneganti, T.D. Converging roles of caspases in inflammasome activation, cell death and innate immunity. Nat. Rev. Immunol., 2016, 16(1), 7-21.
[] [PMID: 26655628]
Chung, H.; Kim, Y.H.; Kwon, M.; Shin, S.J.; Kwon, S.H.; Cha, S.D.; Cho, C.H. The effect of salinomycin on ovarian cancer stem-like cells. Obstet. Gynecol. Sci., 2016, 59(4), 261-268.
[ ] [PMID: 27462592]
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.
Kozak, J.; Wdowiak, P.; Maciejewski, R.; Torres, A. A guide for endometrial cancer cell lines functional assays using the measurements of electronic impedance. Cytotechnology, 2018, 70(1), 339-350.
[] [PMID: 28988392]
Parajuli, B.; Shin, S.J.; Kwon, S.H.; Cha, S.D.; Chung, R.; Park, W.J.; Lee, H.G.; Cho, C.H. Salinomycin induces apoptosis via,
death receptor-5 up-regulation in cisplatin-resistant ovarian cancer cells. Anticancer Res., 2013, 33(4), 1457-1462.
[PMID: 23564786]
Wcisło-Dziadecka, D.; Grabarek, B.; Zmarzły, N. Influence of adalimumab on the expression profile of genes associated with the histaminergic system in the skin fibroblasts in vitro. BioMed Res. Int., 2018, 20181582173
Betel, D.; Wilson, M.; Gabow, A.; Marks, D.S.; Sander, C. The microRNA. org resource: Targets and expression. Nucleic Acids Res.,, 2008, 36 (suppl_1), D149-D153
Zhou, J.; Liu, S.; Wang, Y.; Dai, W.; Zou, H.; Wang, S.; Zhang, J.; Pan, J. Salinomycin effectively eliminates cancer stem-like cells and obviates hepatic metastasis in uveal melanoma. Mol. Cancer, 2019, 18(1), 159.
[ ] [PMID: 31718679]
Kaźmierczuk, A.; Kiliańska, Z.M. Role of heat shock proteins in cell apoptosis. Postepy Hig. Med. Dosw., 2010, 64, 273-283.
Ho, Y.T.; Lu, C.C.; Yang, J.S.; Chiang, J.H.; Li, T.C.; Ip, S.W.; Hsia, T.C.; Liao, C.L.; Lin, J.G.; Wood, W.G.; Chung, J.G. Berberine induced apoptosis via promoting the expression of caspase-8, -9 and -3, apoptosis-inducing factor and endonuclease G in SCC-4 human tongue squamous carcinoma cancer cells. Anticancer Res., 2009, 29(10), 4063-4070.
[PMID: 19846952]
Zhang, Y.; Li, F.; Liu, L.; Jiang, H.; Hu, H.; Du, X.; Ge, X.; Cao, J.; Wang, Y. Salinomycin triggers endoplasmic reticulum stress through ATP2A3 upregulation in PC-3 cells. BMC Cancer, 2019, 19(1), 381.
[ ] [PMID: 31023247]
Fu, C.; Wang, L.; Tian, G.; Zhang, C.; Zhao, Y.; Xu, H.; Su, M.; Wang, Y. Enhanced anticancer effect of oncostatin M combined with salinomycin in CD133+ HepG2 liver cancer cells. Oncol. Lett., 2019, 17(2), 1798-1806.
[PMID: 30675240]
Gao, X.; Zheng, Y.; Ruan, X.; Ji, H.; Peng, L.; Guo, D.; Jiang, S. Salinomycin induces primary chicken cardiomyocytes death via mitochondria mediated apoptosis. Chem. Biol. Interact., 2018, 282, 45-54.
[] [PMID: 29331652]
Vasudevan, S. Posttranscriptional upregulation by microRNAs. Wiley Interdiscip. Rev. RNA, 2012, 3(3), 311-330.
[] [PMID: 22072587]
Kobayashi, N.; Uemura, H.; Nagahama, K.; Okudela, K.; Furuya, M.; Ino, Y.; Ito, Y.; Hirano, H.; Inayama, Y.; Aoki, I.; Nagashima, Y.; Kubota, Y.; Ishiguro, H. Identification of miR-30d as a novel prognostic maker of prostate cancer. Oncotarget, 2012, 3(11), 1455-1471.
[] [PMID: 23231923]
Lin, Z.Y.; Chen, G.; Zhang, Y.Q.; He, H.C.; Liang, Y.X.; Ye, J.H.; Liang, Y.K.; Mo, R.J.; Lu, J.M.; Zhuo, Y.J.; Zheng, Y.; Jiang, F.N.; Han, Z.D.; Wu, S.L.; Zhong, W.D.; Wu, C.L. MicroRNA-30d promotes angiogenesis and tumor growth via MYPT1/c-JUN/VEGFA pathway and predicts aggressive outcome in prostate cancer. Mol. Cancer, 2017, 16(1), 48.
[] [PMID: 28241827]
Zhang, Z.; He, T.; Huang, L.; Ouyang, Y.; Li, J.; Huang, Y.; Wang, P.; Ding, J. Two precision medicine predictive tools for six malignant solid tumors: From gene-based research to clinical application. J. Transl. Med., 2019, 17(1), 405.
[] [PMID: 31796117]
Muhammad, S.; Tang, Q.; Wei, L.; Zhang, Q.; Wang, G.; Muhammad, B.U.; Kaur, K.; Kamchedalova, T.; Gang, Z.; Jiang, Z.; Liu, Z.; Wang, X. miRNA-30d serves a critical function in colorectal cancer initiation, progression and invasion via directly targeting the GNA13 gene. Exp. Ther. Med., 2019, 17(1), 260-272.
[PMID: 30651791]
Soleimani, A.; Khazaei, M.; Ferns, G.A.; Ryzhikov, M.; Avan, A.; Hassanian, S.M. Role of TGF-β signaling regulatory microRNAs in the pathogenesis of colorectal cancer. J. Cell. Physiol., 2019, 234(9), 14574-14580.
[] [PMID: 30684274]
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(1), 556.
[] [PMID: 23176396]
Pileczki, V.; Cojocneanu-Petric, R.; Maralani, M.; Neagoe, I.B.; Sandulescu, R. MicroRNAs as regulators of apoptosis mechanisms in cancer. Clujul Med., 2016, 89(1), 50-55.
[PMID: 27004025]
Torres, A.; Torres, K.; Paszkowski, T.; Radej, S.; Staśkiewicz, G.J.; Ceccaroni, M.; Pesci, A.; Maciejewski, R. Highly increased maspin expression corresponds with up-regulation of miR-21 in endometrial cancer: a preliminary report. Int. J. Gynecol. Cancer, 2011, 21(1), 8-14.
[ ] [PMID: 21330826]
Xu, B.; Xia, H.; Cao, J.; Wang, Z.; Yang, Y.; Lin, Y. MicroRNA-21 inhibits the apoptosis of osteosarcoma cell line SAOS-2 via targeting caspase 8. Oncol. Res., 2017, 25(7), 1161-1168.
[ ] [PMID: 28109080]
Liu, Y.; Ren, L.; Liu, W.; Xiao, Z. MiR-21 regulates the apoptosis of keloid fibroblasts by caspase-8 and the mitochondria-mediated apoptotic signaling pathway via targeting FasL. Biochem. Cell Biol., 2018, 96(5), 548-555.
[] [PMID: 29527928]
Sun, X.; Zhai, H.; Chen, X.; Kong, R.; Zhang, X. MicroRNA-1271 suppresses the proliferation and invasion of colorectal cancer cells by regulating metadherin/Wnt signaling. J. Biochem. Mol. Toxicol., 2018, 32(2)e22028
[] [PMID: 29315995]
Yao, H.; Sun, Q.; Zhu, J. miR-1271 enhances the sensitivity of colorectal cancer cells to cisplatin. Exp. Ther. Med., 2019, 17(6), 4363-4370.
[] [PMID: 31086572]
Xie, F.; Huang, Q.; Liu, C.H.; Lin, X.S.; Liu, Z.; Liu, L.L.; Huang, D.W.; Zhou, H.C. MiR-1271 negatively regulates AKT/MTOR signaling and promotes apoptosis via targeting PDK1 in pancreatic cancer. Eur. Rev. Med. Pharmacol. Sci., 2018, 22(3), 678-686.
[PMID: 29461595]

© 2022 Bentham Science Publishers | Privacy Policy