Abstract
Gain of functional mutations in ras occurs in more than 30% of human malignancies and in particular 90% of pancreatic cancer. Mutant ras, via activating multiple effector pathways, not only promote cell growth or survival, but also apoptosis, depending upon cell types or circumstances. In order to further study the mechanisms of apoptosis induced by oncogenic ras, we employed the ras loop mutant genes and demonstrated that Akt functioned downstream of Ras in human pancreatic cancer or HPNE cells ectopically expressing mutated K-ras for the induction of apoptosis after the concurrent suppression of PKC α and β. In this apoptotic process, the redox machinery was aberrantly switched on in the pancreatic cancer cells as well as prostate cancer DU145 cells. p73 was phosphorylated and translocated to the nucleus, accompanied with UPR activation and induction of apoptosis. The in vitro results were corroborated by the in vivo data. Thus, our study indicated that PKC α and β appeared coping with oncogenic Ras or mutated Akt to maintain the balance of the homeostasis in cancer cells. Once these PKC isoforms were suppressed, the redox state in the cancer cells was disrupted, which elicited persistent oncogenic stress and subsequent apoptotic crisis.
Highlights
Ras proteins exist in two conformations: a GTPbound active state and GDP-bound inactive state
Human pancreatic epithelial cells (HPNE) or its human pancreatic epithelial cells (HPNE) stably transfected with mu-K-ras as well as human pancreatic cell lines Panc-1 or MIA harboring mutated K-ras were used to test their sensitivities to PKC inhibition for the induction of apoptosis
The increased amount of the GTP-bound Ras was detected in all cells expressing aberrant K-ras, in comparison that only the baseline level of active Ras was revealed by the antibody in HPNE cells
Summary
Ras proteins exist in two conformations: a GTPbound active state and GDP-bound inactive state. The ratio of GTP and GDP bound to cellular Ras proteins is controlled by guanine nucleotide exchange proteins and GTPase-activating proteins, the enzymatic activity of which responds to extracellular stimuli (such as growth factors) [1,2,3,4]. GTP-bound Ras interacts with target enzymes/effectors and triggers kinase cascades to regulate various cellular activities. Through controlling the activity of these effectors, is able to influence cell behaviors. PI3K/Akt pathway was shown to be able to upregulate several ROS-related enzymes (such as NADPH oxidase), and play important roles in the regulation of endoplasmic reticulum (ER)stress induced apoptosis [9, 10]
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