A novel HIF-1α/VMP1-autophagic pathway induces resistance to photodynamic therapy in colon cancer cells

Abstract

This is the first report showing that PDT-induced autophagy is directly mediated by HIF-1α and linked to VMP1 as a PDT-induced resistance mechanism.

Abstract

Colon cancer is the third most frequent cancer and the fourth most common cause of cancer-related mortality worldwide and the standard therapy is surgical resection plus adjuvant chemotherapy. Photodynamic therapy (PDT) has been proposed as an adjuvant therapy because it can prevent the tumor recurrence after surgical excision in colon cancer patients. Hypoxia is a common feature in solid tumors and leads to chemo/radioresistance. Recently, it has been shown that in response to hypoxia, cells can induce HIF-1α-mediated autophagy to survive in this hostile microenvironment. Moreover, hypoxia and autophagy have been implicated in the resistance to antitumor PDT. However, the molecular signals by which HIF-1α induces autophagy in the PDT context have not been studied yet. Here we evaluate the interplay between HIF-1α and autophagy as well as the underlying mechanism in the PDT resistance of colon cancer cells. Our study demonstrates that HIF-1α stabilization significantly increases VMP1-related autophagy through binding to hypoxia responsive elements in the VMP1 promoter. We show that HIF-1α-induced autophagy increases colon cancer cell survival as well as decreases cell death after PDT. Moreover, here we demonstrate that HIF-1α-induced autophagy is mediated by VMP1 expression, since the downregulation of VMP1 by the RNA interference strategy reduces HIF-1α-induced autophagy and cell survival after PDT. In conclusion, PDT induces autophagy as a survival mechanism and the induction of the novel HIF-1α/VMP1-autophagic pathway may explain, at least in part, the resistance of colon cancer cells to PDT. The knowledge of the molecular mechanisms involved in PDT resistance may lead to more accurate therapeutic strategies.