Ferroptosis is a type of regulated cell death that displays a promising therapeutic pathway for drug-resistant tumor cells. However, some pancreatic cancer (PC) cells are less sensitive to erastin-induced ferroptosis, and normal pancreatic cells are susceptible to this newly discovered cell death. Therefore, there is an urgent need to find drugs to enhance the sensitivity of these PC cells to erastin while limiting side effects. Here, we found that the oxidized form of vitamin C-dehydroascorbic acid (DHA) can be transported into PC cells expressing high levels of GLUT1, resulting in ferroptosis. Moreover, pharmacological vitamin C combined with erastin can synergistically induce ferroptosis of PC cells involving glutathione (GSH) reduction and ferrous iron accumulation while inhibiting the cytotoxicity of normal cells. Mechanistically, as a direct system Xc- inhibitor, erastin can directly suppress the synthesis of GSH, and the recycling of vitamin C and DHA is performed through GSH consumption, which is denoted as the classical mode. Furthermore, oxidative stress induced by erastin and vitamin C could enhance the expression of HMOX1 via the AMP-activated protein kinase (AMPK)/nuclear factor erythroid 2-related factor 2 (NRF2) pathway to increase the labile iron level, which is named the nonclassical mode. In vivo experiments showed that erastin and vitamin C can significantly slow tumor growth in PC xenografts. In summary, the combination of erastin and vitamin C exerts a synergistic effect of classical and nonclassical modes to induce ferroptosis in PC cells, which may provide a promising therapeutic strategy for PC.

Recent studies have found that hypoxia contributes to tumor progression and drug resistance via inducing exosomes secretion. However, the underlying mechanism of this resistance in pancreatic cancer remains to be explored. In this study, we explored the effect and molecular mechanisms of hypoxia-induced tumor-derived exosomes (Hexo) on stemness and gemcitabine (GEM) resistance in pancreatic cancer cells. Firstly, we discovered that hypoxia could promote the stemness and induce gemcitabine resistance in pancreatic cancer cells. Subsequently, we proved that exosomes secreted by pancreatic cancer cells under normoxic or hypoxic conditions can be transfected into tumor cells. And then, Hexo was demonstrated to promote the proliferation, stemness and Gem resistance of pancreatic cancer cells, as well as inhibit the apoptosis and the cell cycle arrest induced by gemcitabine. Finally, it was verified that Hexo could inactivate the Hippo/YAP pathway of pancreatic cancer cells by transferring exosomal lncROR. In summary, hypoxic tumor microenvironment could promote the stemness and induce gemcitabine resistance in pancreatic cancer cells. Mechanically, Hexo enhanced the stemness to promote chemoresistance of pancreatic cancer cells by transferring lncROR via Hippo signaling. Thus, exosomal lncROR may serve as a candidate target for pancreatic cancer chemotherapy.