Oncotarget

Research Papers:

Suppression of PKC causes oncogenic stress for triggering apoptosis in cancer cells

Suthakar Ganapathy, Bo Peng, Ling Shen, Tianqi Yu, Jean Lafontant, Ping Li, Rui Xiong, Alexandros Makriyannis and Changyan Chen _

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Oncotarget. 2017; 8:30992-31002. https://doi.org/10.18632/oncotarget.16047

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Abstract

Suthakar Ganapathy1,*, Bo Peng1,*, Ling Shen1, Tianqi Yu1, Jean Lafontant1, Ping Li2,3, Rui Xiong3, Alexandros Makriyannis1, Changyan Chen1

1Center for Drug Discovery, Northeastern University, Boston, MA, USA

2The First Affiliated Hospital, Zhengzhou University, Zhengzhou, China

3The Institute of Clinic Sciences, Sahlgrenska Academy, Gothenburg, Sweden

*These authors contributed equally to this work

Correspondence to:

Changyan Chen, email: c.changyan@neu.edu

Keywords: apoptosis, Ras, Akt, ROS, p73

Received: December 21, 2016     Accepted: February 28, 2017     Published: March 09, 2017

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.


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