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Identification of Intracellular Signaling Events Induced in Viable Cells by Interaction with Neighboring Cells Undergoing Apoptotic Cell Death
Published on: December 27, 2016
Suppression of PKC causes oncogenic stress for triggering apoptosis in cancer cells
Suthakar Ganapathy1, Bo Peng1, Ling Shen1
1Center for Drug Discovery, Northeastern University, Boston, MA, USA.
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.
Insights
Oncogenic Ras mutations trigger apoptosis in cancer cells by disrupting cellular redox balance after suppressing PKC alpha and beta. This leads to p73 activation and programmed cell death, offering new therapeutic targets.
Area of Science:
- Oncology
- Molecular Biology
- Cellular Signaling
Background:
- Ras mutations are common in human cancers, particularly pancreatic cancer.
- Mutant Ras activates pathways promoting cell growth, survival, and apoptosis.
- Understanding Ras-induced apoptosis mechanisms is crucial for cancer therapy.
Purpose of the Study:
- To investigate the mechanisms of apoptosis induced by oncogenic Ras.
- To elucidate the role of Protein Kinase C (PKC) isoforms in Ras-mediated apoptosis.
- To identify key signaling events in Ras-induced apoptotic pathways.
Main Methods:
- Utilized ras loop mutant genes in human pancreatic cancer and HPNE cells.
- Investigated the downstream signaling of Ras, including Akt and PKC.
- Analyzed redox machinery, p73 phosphorylation, and Unfolded Protein Response (UPR) activation.
- Corroborated in vitro findings with in vivo data.
Main Results:
- Akt functions downstream of Ras for apoptosis induction upon concurrent suppression of PKC alpha and beta.
- Aberrant activation of the redox machinery and p73 nuclear translocation observed.
- UPR activation accompanied p73 phosphorylation and apoptosis induction.
- PKC alpha and beta suppress oncogenic Ras/mutated Akt effects, maintaining cellular homeostasis.
Conclusions:
- Suppression of PKC alpha and beta disrupts cancer cell redox state, leading to oncogenic stress and apoptosis.
- PKC alpha and beta play a critical role in balancing homeostasis against oncogenic Ras/Akt signaling.
- Targeting PKC isoforms could be a strategy to induce apoptosis in Ras-driven cancers.
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