Decreased sensitivity of several anticancer drugs in TMEPAI knockout triple-negative breast cancer cells
DOI:
https://doi.org/10.13181/mji.v28i2.2687Keywords:
BCRP, MRP1, P-glycoprotein, TMEPAI, triple-negative breast cancer cellAbstract
BACKGROUND Transmembrane prostate androgen-induced protein (TMEPAI) was reported to be highly amplified in the majority of patients with triple-negative breast cancer (TNBC). TMEPAI is related to poorer prognosis, limited treatment options, and prone to drug resistance compared with other proteins. One of the established markers to determine cancer resistance to drugs is the increased expression levels of drug efflux transporters. However, the role of TMEPAI in cancer resistance to drugs has not been elucidated. This study was aimed to investigate whether TMEPAI participates in cancer resistance to drugs by regulating drug efflux transporters.
METHODS TMEPAI knockout (KO) cells were previously developed from a TNBC cell line, Hs578T (wild-type/WT), using a CRISPR-Cas9 system. The expression levels of drug efflux transporters were determined in Hs578T-KO and Hs578-WT by quantitative reverse transcriptase polymerase chain reaction. Cytotoxic concentration 50% (CC50) of several anticancer drugs (doxorubicin, cisplatin, and paclitaxel) were determined in the two cell lines via 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium assay.
RESULTS The results showed that the mRNA expression of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) was significantly increased in Hs578T-KO compared with that in Hs578T-WT cells. CC50 of several anticancer drugs investigated (doxorubicin, paclitaxel, and cisplatin) in Hs578T-KO cells was higher than that in Hs678-WT.
CONCLUSIONS TMEPAI participated in the regulation of mRNA expression levels in drug efflux transporters (P-gp, BCRP, and multidrug resistance-associated protein 1). Further studies are necessary to confirm whether this finding might be dependent on the development of cancer cell sensitivity to anticancer agents.
Downloads
References
Foulkes WD, Smith IE, Reis-Fielho JS. Triple negative breast cancer. N Eng J Med. 2010;363(20):1938-48. https://doi.org/10.1056/NEJMra1001389
Singha PK, Pandeswara S, Geng H, Lan R, Venkatachalam MA, Saikumar P. TGF-v induced TMEPAI/PMEPA1 inhibits canonical Smad signaling through R-Smad sequestration and promotes non-canonical PI3K/Akt signaling by reducing PTEN in triple negative breast cancer. Genes Cancer. 2014;5(9-10):320-36. https://doi.org/10.18632/genesandcancer.30
Krishnamurthy S, Poornima R, Challa VR, Goud YG. Triple negative breast cancer-our experience and review. Indian J Surg Oncol. 2012:3(1):12-6. https://doi.org/10.1007/s13193-012-0138-2
Ng CH, Pathy NB, Taib NA, Teh YC, Mun KS, Amiruddin A, et al. Comparison of breast cancer in Indonesia and Malaysia-a clinico-pathological study between Dharmais Cancer Center Jakarta and University Malaya Medical Center, Kuala Lumpur. Asian Pac J Cancer Prev. 2011;12(11):2943-6.
O'Reilly EA, Gubbins L, Sharma S, Tully R, Guang MH, Weiner-Gorzel K, et al. The fate of chemoresistance in triple negative breast cancer (TNBC). BBA Clin. 2015;3:257-75. https://doi.org/10.1016/j.bbacli.2015.03.003
Xu LL, Shanmugam N, Segawa T, Sesterhenn IA, McLeod DG, Moul JW, et al. A novel androgen-regulated gene, PMEPA1, located on chromosome 20q13 exhibits high level expression in prostate. Genomics. 2000;66(3):257-63. https://doi.org/10.1006/geno.2000.6214
National Center for Biotechnology Information. NCBI[Internet]. Bethesda MD USA: US National Library of Medicine; 2016 [cited 2016 Oct 23]. Available from: https://www.ncbi.nlm.nih.gov/gene/56937.
Giannini G, Ambrosini MI, Di Marcotullio L, Cerignoli F, Zani M, MacKay AR, et al. EGF- and cell-cycle-regulated STAG1/PMEPA1/ERG1.2 belongs to a conserved gene family and is overexpressed and amplified in breast and ovarian cancer. Mol Carcinog. 2003;38(4):188-200. https://doi.org/10.1002/mc.10162
Brunschwig EB, Wilson K, Mack D, Dawson D, Lawrence E, Willson JK, et al. PMEPA1, a transforming growth factor-b-induced marker of terminal colonocyte differentiation whose expression is maintained in primary and metastatic colon cancer. Cancer Res. 2003;63(7):1568-75.
Vo Nguyen TT, Watanabe Y, Shiba A, Noguchi M, Itoh S, Kato M. TMEPAI/PMEPA1 enhances tumorigenic activities in lung cancer cells. Cancer Sci. 2014;105(3):334-41. https://doi.org/10.1111/cas.12355
Watanabe Y, Itoh S, Goto T, Ohnishi E, Inamitsu M, Itoh F, et al. TMEPAI, a transmembrane TGF-v-inducible protein, sequesters Smad proteins from active participation in TGF-v signaling. Mol Cell. 2010;37(1):123-34. https://doi.org/10.1016/j.molcel.2009.10.028
Györffy B, Lanczky A, Eklund AC, Denkert C, Budczies J, Li Q, et al. An online survival analysis tool to rapidly assess the effect of 22,277 genes on breast cancer prognosis using microarray data of 1,809 patients. Breast Cancer Res Treat. 2010;123(3):725-31. https://doi.org/10.1007/s10549-009-0674-9
Wardhani BW, Puteri MU, Watanabe Y, Louisa M, Setiabudy R, Kato M. Knock-out transmembrane prostate androgen-induced protein gene suppressed triple-negative breast cancer cell proliferation. Med J Indones. 2017;26(3):178-82. https://doi.org/10.13181/mji.v26i3.1823
Hu Y, He K, Wang D, Yuan X, Liu Y, Ji H, et al. TMEPAI regulates EMT in lung cancer cells by modulating the ROS and IRS-1 signaling pathways. Carcinogenesis. 2013;34(8):1764-72. https://doi.org/10.1093/carcin/bgt132
Zheng X, Carstens JL, Kim J, Scheible M, Kaye J, Sugimoto H, et al. Epithelial-to-mesenchymal transition is dispensable for metastasis but induces chemoresistance in pancreatic cancer. Nature. 2015;527(7579):525-30. https://doi.org/10.1038/nature16064
Wardhani BW, Puteri MU, Watanabe Y, Louisa M, Setiabudy R, Kato M. TMEPAI genome editing in triple negative breast cancer cells. Med J Indones. 2017;26:14-8. https://doi.org/10.13181/mji.v26i1.1871
Lehmann BD, Bauer JA, Chen X, Sanders ME, Chakravarthy AB, Shyr Y, et al. Identification of human tripple-negative breast cancer subtypes and preclinical models for selection of targeted therapies. J Clin Invest. 2011;121(7):2750-67. https://doi.org/10.1172/JCI45014
Chen WC, Lai Y, Lin YC, Ma JW, Huang LF, Yang NS, et al. Curcumin suppresses doxorubicin-induced epithelial-mesenchymal transition via the inhibition of TGF-v and PI3K/Akt signaling pathways in triple-negative breast cancer cells. J Agric Food Chem. 2013;61(48):11817-24. https://doi.org/10.1021/jf404092f
Thorn CF, Oshiro C, Marsh S, Hernandez-Boussard T, McLeod H, Klein TE, et al. Doxorubicin pathways: pharmacodynamics and adverse effects. Pharmacogenet Genomics. 2011;21(7):440-6. https://doi.org/10.1097/FPC.0b013e32833ffb56
Weaver BA. How taxol/paclitaxel kills cancer cells. Mol Biol Cell. 2014;25(18):2677-81. https://doi.org/10.1091/mbc.e14-04-0916
Dasari S, Tchounwou PB. Cisplatin in cancer therapy: molecular mechanism of action. Eur J Pharmacol. 2014;740:364-78. https://doi.org/10.1016/j.ejphar.2014.07.025
Longley DB, Johnston PG. Molecular mechanisms of drug resistance. J Pathol. 2005;205(2):275-92. https://doi.org/10.1002/path.1706
Oh KT, Baik HJ, Lee AH, Oh YT, Youn YS, Lee ES. The reversal of drug-resistance in tumor using a drug-carrying nanoparticular system. Int J Mol Sci. 2009;10(9):3776-92. https://doi.org/10.3390/ijms10093776
Silva R, Vilas-Boas V, Carmo H, Dinis-Oliveira RJ, Carvalho F, de Lourdes Bastos M, et al. Modulation of P-glycoprotein efflux pump: induction and activation as a therapeutic strategy. Pharmacol Ther. 2015;149:1-123. https://doi.org/10.1016/j.pharmthera.2014.11.013
Bhola NE, Balko JM, Dugger TC, Kuba MG, Sánchez V, Sanders M, et al. TGF-v inhibition enhances chemotherapy action against triple-negative breast cancer. J Clin Invest. 2013;123(3):1348-58. https://doi.org/10.1172/JCI65416
Li L, Wei XH, Pan YP, Li HC, Yang H, He QH, et al. LAPTM4B: a novel cancer-associated gene motivates multidrug resistance through efflux and activating PI3K/AKT signaling. Oncogene. 2010;29(43):5785-95. https://doi.org/10.1038/onc.2010.303
Published
How to Cite
Issue
Section
License
Authors who publish with Medical Journal of Indonesia agree to the following terms:
- Authors retain copyright and grant Medical Journal of Indonesia right of first publication with the work simultaneously licensed under a Creative Commons Attribution-NonCommercial License that allows others to remix, adapt, build upon the work non-commercially with an acknowledgment of the work’s authorship and initial publication in Medical Journal of Indonesia.
- Authors are permitted to copy and redistribute the journal's published version of the work non-commercially (e.g., post it to an institutional repository or publish it in a book), with an acknowledgment of its initial publication in Medical Journal of Indonesia.
