Abstract We have demonstrated that RNA-dependent protein kinase (PKR) and its downstream protein p-eIF2α are independent prognostic markers for survival in lung cancer. In the current study, we aimed to elucidate PKR's specific role in lung cancer. We examined PKR and p-PKR protein expression in 60 frozen primary lung tumor tissues by Western blot analysis and analyzed the association between PKR/p-PKR expression and expression of 139 proteins examined previously by reverse phase protein array in tissue samples from the same 60 patients. We demonstrated several biomarkers that were either positively (p-AMPK) or negatively (IRS1, p-IGF1R, MRE11, ATRIP, telomerase, CHK1, and cyclin E1) correlated with PKR and p-PKR. We confirmed that induction of PKR or p-PKR with expression vectors in lung cancer cells caused phospholation of the AMP-activated protein kinase (AMPK) protein; phospholation was independent of the LKB1, CaMKKβ, and TAK1 pathways. We observed that AMPK phosphorylation was caused by the elevated levels of AMP and decreased levels of ATP resulting from PKR-mediated nutrient depletion. Inhibition of AMPK expression by compound C or siRNA enhanced PKR-mediated cell death. We next investigated the combination of PKR and p-AMPK expression in non-small cell lung cancer patients; we observed that high expression of p-AMPK predicted worse prognosis in patients with high PKR expression but better prognosis in patients with low PKR expression. The p-AMPK may be required for cancer cell survival in patients with high PKR expression and may inhibit cancer cell growth in patients with low PKR expression. In summary, our data indicate that PKR-mediated nutrient depletion induces phosphorylation of AMPK, which is required for lung cancer cell survival. Citation Format: Apar Pataer, Chengcheng Guo, Ruping Shao, Arlene M. Correa, Carmen Behrens, Bingliang Fang, Jack A. Roth, Ignacio I. Wistuba, Stephen G. Swisher. Nutrient depletion caused by PKR induces phosphorylation of AMPK in lung cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4739. doi:10.1158/1538-7445.AM2014-4739
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