Asian Pacific journal of cancer prevention : APJCP · 2026
TMEPAI Confers Paclitaxel Resistance in Triple-Negative Breast Cancer Cells by Promoting AKT Phosphorylation and Its Downstream Cascade.
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Warfvinge Rebecca, Geironson Ulfsson Linda, Dhapola Parashar, Safi Fatemeh, Sommarin Mikael, Soneji Shamit, Hjorth-Hansen Henrik, Mustjoki Satu, Richter Johan, Thakur Ram Krishna, Karlsson Göran
Аннотация
OBJECTIVE: TMEPAI (transmembrane prostate androgen-induced protein) is one of the proteins associated with the resistance of triple-negative breast cancer (TNBC) to various cytotoxic medicines. However, it has remained uncertain how TMEPAI mechanistically contributes to TNBC resistance to paclitaxel. Thus, this study aimed to investigate the effect and possible mechanism of TMEPAI gene editing via CRISPR-Cas9 on the response of triple-negative breast cancer cells to paclitaxel.
METHODS: The present study was conducted on wild-type triple-negative breast cancer cells (BT-549) and BT-549 cells with TMEPAI knocked out using CRISPR-Cas9. Both cell types underwent treatment with TGF-β, followed by paclitaxel, and were evaluated for cell viability and the expression of cell proliferation, apoptosis, drug efflux transporters, and epithelial-mesenchymal transition markers.
RESULT: TMEPAI knock-out cells exhibited a markedly increased susceptibility to paclitaxel, as characterized by decreased viability and elevated expression of pro-apoptotic genes (Bax, caspase-3, caspase-9), as well as a reduction in anti-apoptotic markers (Bcl-2). The presence of TMEPAI perpetuated the phosphorylation of AKT (pAKT/AKT), elevated the expression of drug efflux transporters (particularly P-glycoprotein and MRP-1), and facilitated epithelial-mesenchymal transition (EMT), as evidenced by increased levels of Snail, Zeb1, and Twist. All these effects were diminished in TMEPAI-knock-out triple-negative breast cancer cells.
CONCLUSION: TMEPAI appears to facilitate paclitaxel resistance in triple-negative breast cancer cells by promoting cell survival signaling, inhibiting apoptosis, enhancing drug efflux, and initiating epithelial-mesenchymal transition (EMT). Targeting TMEPAI may be a viable approach to overcoming resistance and improving treatment outcomes in triple-negative breast cancer cells.
METHODS: The present study was conducted on wild-type triple-negative breast cancer cells (BT-549) and BT-549 cells with TMEPAI knocked out using CRISPR-Cas9. Both cell types underwent treatment with TGF-β, followed by paclitaxel, and were evaluated for cell viability and the expression of cell proliferation, apoptosis, drug efflux transporters, and epithelial-mesenchymal transition markers.
RESULT: TMEPAI knock-out cells exhibited a markedly increased susceptibility to paclitaxel, as characterized by decreased viability and elevated expression of pro-apoptotic genes (Bax, caspase-3, caspase-9), as well as a reduction in anti-apoptotic markers (Bcl-2). The presence of TMEPAI perpetuated the phosphorylation of AKT (pAKT/AKT), elevated the expression of drug efflux transporters (particularly P-glycoprotein and MRP-1), and facilitated epithelial-mesenchymal transition (EMT), as evidenced by increased levels of Snail, Zeb1, and Twist. All these effects were diminished in TMEPAI-knock-out triple-negative breast cancer cells.
CONCLUSION: TMEPAI appears to facilitate paclitaxel resistance in triple-negative breast cancer cells by promoting cell survival signaling, inhibiting apoptosis, enhancing drug efflux, and initiating epithelial-mesenchymal transition (EMT). Targeting TMEPAI may be a viable approach to overcoming resistance and improving treatment outcomes in triple-negative breast cancer cells.