Combined inhibition of autophagy and Nrf2 signaling augments bortezomib-induced apoptosis by increasing ROS production and ER stress in pancreatic cancer cells

Abstract

Pancreatic cancer (PC) is highly resistant to current therapies; thus, there is an urgent need to develop new treatment strategies. The proteasome is crucially important for proteostasis, which is involved in cell proliferation and survival, making it an attractive therapeutic target in cancer. However, recent studies have indicated that bortezomib, a highly selective proteasome inhibitor, has limited effects in solid tumors including PC. Thus, more mechanistic insights into chemo-sensitization strategies for bortezomib are urgently needed. Herein, we demonstrate that bortezomib induced apoptosis and autophagy via a mechanism involving endoplasmic reticulum (ER) stress in PC cells. Additionally, bortezomib treatment led to increased levels of intracellular reactive oxygen species (ROS), which play critical roles in bortezomib-induced ER stress and apoptosis. Moreover, autophagy functions as a compensatory mechanism to eliminate bortezomib-induced ROS and resists ER stress-mediated apoptosis. Additionally, the Nrf2-mediated antioxidative response, which works against with bortezomib-induced autophagy, also protected cells against bortezomib-induced ROS production. Finally, the dual inhibition of autophagy and Nrf2 signaling cooperatively enhanced bortezomib-induced apoptosis by elevating ROS levels and ER stress. Together, these data demonstrate that activation of autophagy and the Nrf2 antioxidant system, which lowers intracellular ROS, are mechanistically how PC cells overcome bortezomib treatment. In summary, combining proteasome inhibitors with drugs targeting autophagy and Nrf2 signaling could be a promising therapeutic approach for PC treatment.

Reactive oxygen species mediate anlotinib-induced apoptosis via activation of endoplasmic reticulum stress in pancreatic cancer

“…When cells are subjected to strong external environmental stress, the unfolded or misfolded proteins accumulate in the ER, causing ER stress. Many drugs, such as bortezomib 17 , suffruticosa aqueous extracts 32 and apatinib 18 , cause ER stress and then induce apoptosis. Similar to these reports, our study also found that anlotinib induced increases in BiP, PERK and CHOP, which are ER stress biomarker proteins.…”

“…ATF4 then triggers apoptosis via activating CHOP, a promotive apoptosis protein that is involved in cell stress and induces cell cycle arrest 16 . In cancer treatment, ER stress is a common process that many antitumour drugs exploit to induce apoptosis in cancer cells, such as bortezomib 17 and apatinib (a TKI) 18 . Hence, we suspected whether anlotinib has a similar mechanism against PC.…”

TAF1L promotes development of oral squamous cell carcinoma via decreasing autophagy-dependent apoptosis

“…To avoid cell apoptosis is a typical characteristic in the most of cancers. Moreover, cell autophagy and apoptosis were pivotal regulation in the development of cancer, which could result in the severity of canceration [41,42]. Increasing numbers of research has demonstrated that chemotherapeutic and Figure 5.…”

Lipid Accumulation and Injury in Primary Calf Hepatocytes Challenged With Different Long-Chain Fatty Acids

“…Mitochondrial activities, including beta-oxidation of free fatty acids, production of ATP, and ROS are all central to homeostatic regulation of lipid and energy metabolism in hepatocytes (32). In addition, compounds such as ROS are important for the regulation of apoptosis (33). In vitro, compared with OA, exogenous PA led to greater ROS accumulation in rat hepatoma cells, a response partly caused by the inability of mitochondria to handle large amounts of exogenous long-chain fatty acids, which often leads to mitochondrial dysfunction (34,35).…”