Autophagy inhibitor chloroquine increases sensitivity to cisplatin in QBC939 cholangiocarcinoma cells by mitochondrial ROS

Abstract

The tumor cells have some metabolic characteristics of the original tissues, and the metabolism of the tumor cells is closely related to autophagy. However, the mechanism of autophagy and metabolism in chemotherapeutic drug resistance is still poorly understood. In this study, we investigated the role and mechanism of autophagy and glucose metabolism in chemotherapeutic drug resistance by using cholangiocarcinoma QBC939 cells with primary cisplatin resistance and hepatocellular carcinoma HepG2 cells. We found that QBC939 cells with cisplatin resistance had a higher capacity for glucose uptake, consumption, and lactic acid generation, and higher activity of the pentose phosphate pathway compared with HepG2 cells, and the activity of PPP was further increased after cisplatin treatment in QBC939 cells. It is suggested that there are some differences in the metabolism of glucose in hepatocellular carcinoma and cholangiocarcinoma cells, and the activation of PPP pathway may be related to the drug resistance. Through the detection of autophagy substrates p62 and LC3, found that QBC939 cells have a higher flow of autophagy, autophagy inhibitor chloroquine can significantly increase the sensitivity of cisplatin in cholangiocarcinoma cells compared with hepatocellular carcinoma HepG2 cells. The mechanism may be related to the inhibition of QBC939 cells with higher activity of the PPP, the key enzyme G6PDH, which reduces the antioxidant capacity of cells and increases intracellular ROS, especially mitochondrial ROS. Therefore, we hypothesized that autophagy and the oxidative stress resistance mediated by glucose metabolism may be one of the causes of cisplatin resistance in cholangiocarcinoma cells. It is suggested that according to the metabolism characteristics of tumor cells, inhibition of autophagy lysosome pathway with chloroquine may be a new route for therapeutic agents against cholangiocarcinoma.

Poly(adenosine diphosphate ribose) polymerase inhibitors induce autophagy‐mediated drug resistance in ovarian cancer cells, xenografts, and patient‐derived xenograft models

“…In accordance with these results, Qu et al 27 showed that CQ increases the sensitivity to cisplatin in cholangiocarcinoma cells by increasing ROS. Consequently, the cause of apoptosis induction in the combination treatment might be related to the increase in DNA damage and the accumulation of ROS.…”

“…Consequently, the cause of apoptosis induction in the combination treatment might be related to the increase in DNA damage and the accumulation of ROS. In accordance with these results, Qu et al 27 showed that CQ increases the sensitivity to cisplatin in cholangiocarcinoma cells by increasing ROS. Also, Ganguli et al 28 found that inhibition of autophagy by CQ potentiates the anticancer properties of artemisinin by promoting ROS-dependent apoptosis.…”

Inhibition of PI3K/mTOR increased the sensitivity of hepatocellular carcinoma cells to cisplatin via interference with mitochondrial‐lysosomal crosstalk

“…[13][14][15] This finding provides support for mitochondria as targets of cisplatin in HCC because these organelles are the major sites of ROS formation in the cell, 16,17 and the production of mitochondrial ROS (mtROS) is an important indicator of damaged mitochondrial antioxidant defence function. [13][14][15] This finding provides support for mitochondria as targets of cisplatin in HCC because these organelles are the major sites of ROS formation in the cell, 16,17 and the production of mitochondrial ROS (mtROS) is an important indicator of damaged mitochondrial antioxidant defence function.…”

“…This mechanism could be developed as a novel target for treatment of HCC in the future.This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.Several studies, including our own, have reported that cisplatin enhanced the reactive oxygen species (ROS) levels in HCC cells. [13][14][15] This finding provides support for mitochondria as targets of cisplatin in HCC because these organelles are the major sites of ROS formation in the cell, 16,17 and the production of mitochondrial ROS (mtROS) is an important indicator of damaged mitochondrial antioxidant defence function. 18 Furthermore, low mtROS levels can activate the mitophagy-lysosome pathway to degrade damaged mitochondria and mtROS.…”

MicroRNA-337-3p suppresses cell viability, apoptosis, and autophagy by modulating PPARγ expression in androgen-dependent human prostate cancer

“…Blessing et al reported the importance of autophagy in the progression of PCa, demonstrated the mechanism of enhanced autophagy, and proposed that autophagy has potential for treating advanced PCa (Blessing et al 2017). Many studies have indicated that pharmacologically suppressing autophagy with agents such as chloroquine and metformin, as well as the agents described herein, could enhance the cell-killing effect of cancer therapeutic agents (Qu et al 2017;Yoshida 2017;Kotcherlakota et al 2018).…”