Identification of thioredoxin-interacting protein 1 as a hypoxia-inducible factor 1 alpha-induced gene in pancreatic cancer

Objective: To investigate the expression of thioredoxin-interacting protein (TXNIP) during hypoxia and its dependency on hypoxia-inducible factor 1 alpha ( HIF-1 alpha) in pancreatic cancer cell lines. Methods: MiaPaCa-2 pancreatic cancer cells were transiently transfected with siRNA to HIF-1 alpha and TXNIP protein measured after growth in normoxia or hypoxia. In addition, HIF-1 alpha dependency was assessed by transiently transfecting MiaPaCa-2 pancreatic cancer cells with a mutated oxygen degradation domain resulting in stable HIF-1 alpha expression in normoxic conditions. Panc-1 pancreatic cancer cells with low endogenous TXNIP expression were stably transfected with TXNIP, and cell survival and response to platinum cancer agents were tested. Quantitative immunohistochemistry was utilized to measure the expression of TXNIP and thioredoxin 1 in human pancreatic cancer tissues. Results: Thioredoxin-interacting protein was induced during hypoxia in pancreatic cancer cells in a HIF-1 alpha dependent manner. Overexpression of TXNIP in the Panc-1 cells resulted in a higher basal apoptosis and increased sensitivity to cisplatin and oxaliplatin. A negative correlation was observed between TXNIP and thioredoxin 1 expression in human pancreatic cancer tissues. Conclusions: Thioredoxin-interacting protein, a putative tumor suppressor gene, is induced in response to hypoxia in a HIF-1 alpha-dependent manner in pancreatic cancer cells, resulting in increased apoptosis and increased sensitivity to platinum anticancer therapy. Increased TXNIP may be a mechanism to counterbalance the prosurvival effects of HIF-1 alpha.