Interplay between autophagy and apoptosis in pancreatic tumors in response to gemcitabine

Abstract

Pancreatic cancer is an aggressive disease. Its incidence has increased over the last two decades. It is currently the fourth cause of death among cancers in the western world. Unfortunately, systemic chemotherapy still relies on just a few drugs which until now have produced unsatisfactory results. Gemcitabine (2'-2'-difluorodeoxycytidine) is currently the standard chemotherapy treatment at all stages of pancreatic adenocarcinoma. Survival benefit and clinical impact however remain moderate due to a high degree of intrinsic and acquired resistance. Autophagy plays an important role in cell death decision but can also protect cells from various apoptotic stimuli. We investigated the function of autophagy in pancreatic carcinoma cells, which are frequently insensitive to standard chemotherapeutic agents. Here, we demonstrate that autophagy is one of the mechanisms responsible for the refractory response of pancreatic tumors to gemcitabine. We present evidence in vitro and in vivo that proves autophagy plays a protective role in pancreatic ductal carcinoma cells, preventing them from entering the apoptotic pathway after stimulus with gemcitabine, thus contributing to treatment resistance. A better understanding of the role in the process may help in the discovery of new strategies to overcome tumor drug resistance in this aggressive disease.

Safety and Biologic Response of Pre-operative Autophagy Inhibition in Combination with Gemcitabine in Patients with Pancreatic Adenocarcinoma

“…The murine models evaluated by Rosenfeldt et al only examined the impact of autophagy inhibition during carcinogenesis. Additionally, these studies did not use chemotherapy in combination with autophagy inhibitors, which is known to further promote the survival pathway of autophagy (37-39). We and others have not observed promotion of tumor growth either in vitro or in vivo with autophagy inhibition (5, 7, 8, 40, 41).…”

Potential of adenovirus‐mediated REIC/Dkk‐3 gene therapy for use in the treatment of pancreatic cancer

“…Autophagy is a catabolic membrane‐trafficking process activated by various cellular stressors . Autophagy has been reported to promote the survival of cancer cells and contribute to the development of tolerance to chemotherapy . On the other hand, autophagy has also been reported to suppress tumor growth .…”

“…30 Autophagy has been reported to promote the survival of cancer cells and contribute to the development of tolerance to chemotherapy. [30][31][32][33][34] On the other hand, autophagy has also been reported to suppress tumor growth. 35,36 Although the effects of autophagy remain controversial, the inhibition of autophagy is believed to be beneficial for cancer therapy.…”

Cellular and molecular aspects of pancreatic cancer

“…Pancreatic cancer cells build resistance to gemcitabine. One mechanism of resistance is autophagy in response to the drug, which prevents the cells from entering the apoptotic pathway (Papademetrio et al, 2014). …”