Chemotherapy-induced apoptosis in pancreatic cancer with mutant p53 involves p73 and is mediated via the extrinsic and the intrinsic pathway

Introduction: Pancreatic cancer is associated with low responsiveness to conventional chemotherapies. The development of up to 70% of pancreatic carcinomas has been shown to be associated with a loss of p53 function.

Like p53, TAp63 and TAp73 activate genes exerting roles in different steps of the apoptosis signalling program. The dominant-negative isoforms of p63 and p73 (deltaNp63, deltaNp73) can oppose the transactivation- and pro-apoptotic capabilities of the full length (TA) isoforms.

Aim: Our aim was to analyze the downstream mechanisms by which chemotherapeutic drugs elicit apoptosis in pancreatic carcinoma cells with mutation/inactivation of the p53 signalling pathway (BxPC-3).

Results: Chemotherapeutic treatment (5-FU, Gemcitabine and Oxaliplatin) resulted in the accumulation of endogenous p73 in BxPC-3 cells, which due to a mutation in p53 are defective in the p53-dependent DNA damage response. Consequently, chemotherapy-induced accumulation of p73 led to apoptosis in a dose- and time-dependent manner. Of clinical importance, blocking p73 function by overexpression of the dominant negative p73 or the use of siRNA conferred protection against chemotherapy-induced apoptosis. Furthermore we could show that chemotherapeutic drugs via accumulation of endogenous p73 engage multiple apoptosis pathways stimulating death receptor signalling, activation of caspases and apoptosis emanating from mitochondria. These findings indicate that p73 may substitute for a mutated/inactivated p53 in the induction of the chemotherapy-induced DNA damage response pathway in pancreatic cancer.

Conclusion: Our findings demonstrate a link between chemotherapy, accumulation of endogenous p73 and the induction of the extrinsic and intrinsic apoptosis signalling pathway in a pancreatic cancer cell line with mutated p53 status. Conversely, we show that disruption of the p73 pathway plays an oncogenic role and contributes to chemoresistance. Reconstitution of p53 activity in p53-deficient or -mutated tumors has been demonstrated to be feasible and practical. Interfering with the expression or function of deltaNp73 and/or inactivated p73 may provide new treatment options especially in pancreatic carcinomas with inactivated p53.