Fluorinated thiazolidinol drives autophagic cell death in pancreatic cancer cells via AMPK activation and perturbation of critical sentinels of oncogenic signaling

摘要

Pancreatic cancer is one of the most malignant cancers around the world. The co-occurrence of mutation in KRAS and p53 makes it highly aggressive, proliferative, metastatic, and resistant to apoptotic cell death. Therefore, there is a need to trigger an alternate mechanism of cancer cell death in apoptosis-resistant pancreatic cancer. Autophagic cell death could be an alternate viable option for treatment in such cases. Thus, the identification of small molecules as autophagy modulators with potent anticancer efficacy would be of great importance in pancreatic cancer. The present study investigates fluorinated thiazolidionol (FTZ) driven autophagy modulation, underlying mechanism, and regulation of critical sentinels of oncogenic signaling in pancreatic cancer cells. We identified that FTZ triggered autophagic cell death in pancreatic cancer cells, independent of apoptosis evidenced by an increase in cytoplasmic vacuoles formation, autophagy flux, LC3-II expression, and p62 degradation. Further, the crucial events of apoptosis i.e., Caspase-3 activation and PARP cleavage, were not observed, indicating the non-occurrence of apoptotic cell death. Moreover, FTZ was able to activate AMPK and suppress PI3k/ Akt/mTOR as well as MEK/ERK, the key oncogenic signaling pathways in cancer cells. Furthermore, treatment with FTZ suppressed migration, invasion, and angiogenesis in pancreatic cancer cells. Studies in vivo revealed significant regression of tumors by FTZ in nude mice model. Overall, our study demonstrates that FTZ induces autophagic cell death in pancreatic cancer cells independent of apoptosis, which is accompanied by AMPK activation and suppression of critical sentinels of oncogenic signaling in pancreatic cancer cells.