Phenylethyl isothiocyanate reverses cisplatin resistance in biliary tract cancer cells via glutathionylation-dependent degradation of Mcl-1

Abstract

Biliary tract cancer (BTC) is a highly malignant cancer. BTC exhibits a low response rate to cisplatin (CDDP) treatment, and therefore, an understanding of the mechanism of CDDP resistance is urgently needed. Here, we show that BTC cells develop CDDP resistance due, in part, to upregulation of myeloid cell leukemia 1 (Mcl-1). Phenylethyl isothiocyanate (PEITC), a natural compound found in watercress, could enhance the efficacy of CDDP by degrading Mcl-1. PEITC-CDDP co-treatment also increased the rate of apoptosis of cancer stem-like side population (SP) cells and inhibited xenograft tumor growth without obvious toxic effects. In vitro, PEITC decreased reduced glutathione (GSH), which resulted in decreased GSH/oxidized glutathione (GSSG) ratio and increased glutathionylation of Mcl-1, leading to rapid proteasomal degradation of Mcl-1. Furthermore, we identified Cys16 and Cys286 as Mcl-1 glutathionylation sites, and mutating them resulted in PEITC-mediated degradation resistant Mcl-1 protein. In conclusion, we demonstrate for the first time that CDDP resistance is partially associated with Mcl-1 in BTC cells and we identify a novel mechanism that PEITC can enhance CDDP-induced apoptosis via glutathionylation-dependent degradation of Mcl-1. Hence, our results provide support that dietary intake of watercress may help reverse CDDP resistance in BTC patients.

FBXW7 modulates malignant potential and cisplatin‐induced apoptosis in cholangiocarcinoma through NOTCH1 and MCL1

“…Myeloid cell leukemia sequence 1 is a FBXW7 substrate that is associated with CDDP resistance in several types of malignancy . To determine whether MCL1 is regulated by FBXW7 in CC cells treated with CDDP, we analyzed MCL1 levels in FBXW7‐depleted CC cells by immunoblotting.…”

“…The current standard for chemotherapy in advanced and recurrent CC is the combination of GEM and CDDP, but its efficacy is limited due to the development of chemoresistance, the mechanisms of which are not well understood. Several studies have, however, described the relationship between CDDP resistance and the accumulation of MCL1 . Unlike other B‐cell lymphoma two family members, MCL1 is unstable and provides a mechanism for cells to shift from survival to apoptosis in response to stressors .…”

“…Cholangiocarcinoma cells are resistant to chemotherapeutic agents such as CDDP, accounting for the poor prognosis of CC . Several studies have described the relationship between the mechanism of CDDP resistance and the accumulation of MCL1 .…”

Overcoming resistance to mitochondrial apoptosis by BZML‐induced mitotic catastrophe is enhanced by inhibition of autophagy in A549/Taxol cells

“…The GSH/GSSG ratio is widely used as an important indicator to evaluate the cellular redox system . As shown in Figure A, the GSH/GSSG ratios were significantly reduced in both BZML‐treated A549 and A549/Taxol cells.…”

“…In contrary, GSH, an ROS scavenger, plays a protective role against oxidative agents and leads to apoptosis resistance in cancer cells by eliminating intracellular ROS . Additionally, GSH‐based detoxification also causes apoptosis resistance in numerous cancer cells . Thus, excessive ROS production along with GSH depletion can effectively enhance anti‐cancer drug activity and overcome drug resistance …”