Abstract
Pancreatic cancer is a devastating human malignancy and gain of functional mutations in K-ras oncogene is observed in 75%–90% of the patients. Studies have shown that oncogenic ras is not only able to promote cell growth or survival, but also apoptosis, depending upon circumstances. Using pancreatic cancer cell lines with or without expressing mutated K-ras, we demonstrated that the inhibition of endogenous PKC activity sensitized human pancreatic cancer cells (MIA and PANC-1) expressing mutated K-ras to apoptosis, which had no apoptotic effect on BxPC-3 pancreatic cancer cells that contain a normal Ras as well as human lung epithelial BAES-2B cells. In this apoptotic process, the level of ROS was increased and PUMA was upregulated in a p73-dependent fashion in MIA and PANC-1 cells. Subsequently, caspase-3 was cleaved. A full induction of apoptosis required the activation of both ROS- and p73-mediated pathways. The data suggest that PKC is a crucial factor that copes with aberrant K-ras to maintain the homeostasis of the pancreatic cancer cells harboring mutated K-ras. However, the suppression or loss of PKC disrupts the balance and initiates an apoptotic crisis, in which ROS and p73 appear the potential, key targets.
Highlights
Pancreatic cancer is a disease with a dismal outlook
Since K-ras mutations are detected in most of pancreatic adenocarcinoma lesions [1], it led us to examine the susceptibility of pancreatic cancer cells to apoptosis in response to the treatment with GO6976
It is known that gain of functional mutations in K-ras occur at early stages in human pancreatic cancer patients or mouse models that were generated by knockout of tumor suppressor genes of p16, Arf, or p53, respectively or in combinations [12,13,14]
Summary
Pancreatic cancer is a disease with a dismal outlook. In the United States, approximately 33,000 patients are diagnosed with pancreatic cancer each year and almost an equal number will die from this malignant disease [1,2,3]. Pancreatic cancer causes a significant numbers of deaths annually. Several features of this devastating disease are responsible for the high rate of mortality, due to the difficulty to detect precursor lesions or noticing the symptoms until in the advanced stages. Advanced pancreatic cancer is often resistant to conventional chemotherapy or radiotherapy. All of these indicate the urgency for developing new strategies to treat this fatal disease
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