Autophagy inhibits chemotherapy-induced apoptosis through downregulating Bad and Bim in hepatocellular carcinoma cells

Abstract

The tumor microenvironment, including ischemia, has been increasingly recognized as a critical factor in the process of tumor development. Hypoxia and nutrient deficiency resulting from ischemia widely exist in solid tumors. Recent studies have shown that hypoxia and nutrient deficiency contribute to chemoresistance by inducing autophagy, but the underlying mechanism remains unknown. This study aimed to explore the role of autophagy induced by low glucose and hypoxia (LH) in the chemoresistance of hepatocellular carcinoma cells. Our results demonstrated that LH induced autophagy and downregulated Bad and Bim in hepatocellular carcinoma cells. The inhibition of autophagy reversed the reduction of these pro-apoptotic factors during the LH treatment. Furthermore, Bad and Bim were also significantly downregulated by autophagy during the process that LH promoted the chemoresistance of hepatocellular carcinoma cells. In addition, RNAi or the overexpression of Bad and Bim can significantly reduce or increase chemotherapy-induced cell death, respectively. Taken together, these data indicate that the downregulation of Bad and Bim plays a significant role in the autophagy-induced chemoresistance of hepatocellular carcinoma cells.

The multi-targeted tyrosine kinase inhibitor vandetanib plays a bifunctional role in non-small cell lung cancer cells

“…In addition, we speculat that vandetanib may also play a protective role in NSCLC cells that accompanies its antitumor activity. Our previous work demonstrated that autophagy contributes to the chemoresistance of hepatocellular carcinoma cells19. Autophagy has been shown to be a mechanism of resistance to several chemotherapeutic agents, such as tyrosine kinase inhibitors and monoclonal antibodies targeting the EGFR and VEGFR signaling pathways in multiple solid tumor models including NSCLC.…”

Paclitaxel resistance development is associated with biphasic changes in reactive oxygen species, mitochondrial membrane potential and autophagy with elevated energy production capacity in lung cancer cells: A chronological study

“…The reasons behind development of Tx resistance are many which include changes in expressions of the target molecule, tubulin (βIII tubulin over expression), 22 increase in expressions of drug efflux pumps like MDR-1, changes in expressions of proteins involved in regulation of apoptotic pathways and mitotic checkpoint proteins, 45 and increased ability of the cancer cells to survive under stressed condition with the help of autophagy. 11 There are various studies of characterisation of Tx-resistant cells in different cancer cell lines; 6,46 however, detail time point study of changes in cancer cells in the course of Tx resistance development has not been reported. Since such time point studies of resistance development in patients and animals are out of scope, therefore, understanding in detail the changes that occur in lung cancer cells with time in the way of development of resistance against Tx could help us in better management of the disease and also aid in prevention of resistance development against Tx.…”

“…9 In early phase, autophagy acts as tumour suppressor, 10 while in later stage, autophagy helps cancer cells to survive under various stressed conditions including chemotherapy. 11 Thus, understanding the behavioural role of autophagy in process of chemoresistance development against Tx is essential. Other important factors that aid in Tx resistance development are over-expression of drug efflux pumps (like MDR1, MRP1), 12,13 which actively pumps out the drug molecules from the cells there by lowering the affectivity of the drug attributing in Tx resistance.…”

Molecular mechanisms for tumour resistance to chemotherapy

“…It is commonly thought that chemoresistance results from activation of autophagy and subsequent inhibition of apoptosis and elevation of autophagy is often linked to decreased apoptosis . This process can be mediated through down‐regulating Bad and Bim which are both pro‐apoptosis proteins . Both autophagy and apoptosis may share common upstream signals mediated by p38‐MAPK and JNK, and these MAPKs play a key role in regulating the balance between autophagy and apoptosis involved in chemoresistance .…”