Oncotarget

Research Papers:

RNA-dependent protein kinase (PKR) depletes nutrients, inducing phosphorylation of AMP-activated kinase in lung cancer

Chengcheng Guo, Chuncheng Hao, RuPing Shao, Bingliang Fang, Arlene M. Correa, Wayne L. Hofstetter, Jack A. Roth, Carmen Behrens, Neda Kalhor, Ignacio I. Wistuba, Stephen G. Swisher and Apar Pataer _

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Oncotarget. 2015; 6:11114-11124. https://doi.org/10.18632/oncotarget.3573

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Abstract

Chengcheng Guo1,5, Chuncheng Hao1,6, RuPing Shao1, Bingliang Fang1, Arlene M. Correa1, Wayne L. Hofstetter1, Jack A. Roth1, Carmen Behrens2, Neda Kalhor3, Ignacio I. Wistuba4, Stephen G. Swisher1 and Apar Pataer1

1 Departments of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

2 Thoracic Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

3 Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

4 Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

5 Current address: Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangzhou, China

6 Current address: Department of Oncology Radiotherapy, The Cancer Hospital of Harbin Medical University, Harbin, Heilongjiang, People’s Republic of China

Correspondence to:

Apar Pataer, email:

Keywords: PKR, AMPK, nutrient depletion, lung cancer

Received: February 05, 2015 Accepted: February 22, 2015 Published: March 14, 2015

Abstract

We have demonstrated that RNA-dependent protein kinase (PKR) and its downstream protein p-eIF2α are independent prognostic markers for overall survival in lung cancer. In the current study, we further investigate the interaction between PKR and AMPK in lung tumor tissue and cancer cell lines. We examined PKR protein expression in 55 frozen primary lung tumor tissues by Western blotting and analyzed the association between PKR expression and expresson of 139 proteins on tissue samples examined previously by Reverse Phase Protein Array (RPPA) from the same 55 patients. We observed that biomarkers were either positively (phosphorylated AMP-activated kinaseT172 [p-AMPK]) or negatively (insulin receptor substrate 1, meiotic recombination 11, ATR interacting protein, telomerase, checkpoint kinase 1, and cyclin E1) correlated with PKR. We further confirmed that induction of PKR with expression vectors in lung cancer cells causes activation of the AMPK protein independent of the LKB1, TAK1, and CaMKKβ pathway. We found that PKR causes nutrient depletion, which increases AMP levels and decreases ATP levels, causing AMPK phosphorylation. We further demonstrated that inhibiting AMPK expression with compound C or siRNA enhanced PKR-mediated cell death. We next explored the combination of PKR and p-AMPK expression in NSCLC patients and observed that expression of p-AMPK predicted a poor outcome for adenocarcinoma patients with high PKR expression and a better prognosis for those with low PKR expression. These findings were consistent with our in vitro results. AMPK might rescue cells facing metabolic stresses, such as ATP depletion caused by PKR. Our data indicate that PKR causes nutrient depletion, which induces the phosphorylation of AMPK. AMPK might act as a protective response to metabolic stresses, such as nutrient deprivation.


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