C Western blot analysis of BCAT1 protein expression in Hela and HepG2 cell lines. B Western blot analysis of BCAT1 and p53 protein expression in Hela and HepG2 cells treated with cisplatin (20 and 10 μM, respectively) for 24 h. Hela cells were treated with 20 μM cisplatin and HepG2 cells were treated with 10 μM cisplatin for 24 h. These findings demonstrate a new mechanism, revealing that BCAT1 decreases cisplatin sensitivity in cancer cells by inducing mTOR-mediated autophagy via branched-chain amino acid leucine metabolism, providing an attractive pharmacological target to improve the effectiveness of chemotherapy.Ī qRT-PCR was performed to detect BCAT1 mRNA expression in Hela and HepG2 cells treated with cisplatin. Also, the knockdown of BCAT1 or the administration of leucine activated mTOR signaling, inhibited autophagy, and increased cisplatin sensitivity in cancer cells in vivo. Moreover, inhibition of autophagy by chloroquine increased cisplatin sensitivity in vivo. In addition, branched-chain amino acids or leucine treatment inhibited cisplatin- or BCAT1-mediated autophagy and increased cisplatin sensitivity by activating mTOR signaling in cancer cells.
The cisplatin-induced up-regulation of BCAT1 decreased the cisplatin sensitivity by regulating autophagy through the mTOR signaling pathway. In this study, we revealed that cisplatin triggered autophagy in cancer cells, with an increase in BCAT1 expression. However, the exact role and mechanism of how BCAT1 is involved in cisplatin cytotoxicity remain undefined. Our previous studies demonstrated that BCAT1 promoted cell proliferation and decreased cisplatin sensitivity in HCC cells. Cisplatin is one of the most effective chemotherapy drugs and is widely used in the treatment of cancer, including hepatocellular carcinoma (HCC) and cervical cancer, but its therapeutic benefit is limited by the development of resistance.
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