Prognostic value of PKR and AMPK in NSCLC patients

We next analyzed the effects of the combination of PKR and p-AMPK on the overall survival of 299 NSCLC patients (194 adenocarcinoma and 105 squamous cell carcinoma). We used PKR and p-AMPK levels to stratify patients into four groups: those with high expression of PKR and with p-AMPK expression; those with high PKR expression and without p-AMPK expression; those with low PKR expression and with p-AMPK expression; and those with low PKR expression and without p-AMPK expression. Among the four stratified groups, overall survival did not differ significantly for squamous cell carcinoma patients (P = 0.18; Figure 5A); however, adenocarcinoma patients did have significantly different overall survival (P < 0.0001, Figure 5B). Among 194 adenocarcinoma patients, 72 PKRHigh/p-AMPKPositive patients had slightly worse overall survival than did 34 PKRHigh/p-AMPKNegative patients (Figure 5B and 5C). In addition, we observed that 50 PKRLow/p-AMPKPositive patients had better overall survival than did 38 PKRLow/p-AMPKNegative patients (Figure 5B and 5D). Representative images of PKR and p-AMPK expression in the cytoplasm of NSCLC cells are shown in Figure 5E. We also determined the PKR-p-AMPK relationship using Fisher’s exact test and Spearman’s correlation coefficient. We have demonstrated that PKR is positively correlated with p-AMPK in patients’ samples (Spearman’s rho=0.12; P = 0.03). Univariate and multivariate Cox proportional hazards regression analysis revealed that pathologic stage and PKR/p-AMPK expression significantly affected overall survival (Data not shown). Our results suggest that p-AMPK may promote tumor growth in adenocarcinoma patients with high PKR expression and may suppress tumor growth in adenocarcinoma patients with low PKR expression.

Figure 5: The prognostic significance assessed with Kaplan-Meier survival estimates and log-rank test. (A-E) Kaplan-Meier survival curves showing the differences in survival duration using PKR combined with phosphorylated (p-)AMPK in all stages of squamous cell carcinoma (SCC) (A) and adenocarcinoma (ADC) (B-D) lung cancer patients. The survival rate in ADC patients with PKRlow/p-AMPKnegative was significantly lower than that in ADC patients with PKRlow/p-AMPKpositive, ADC patients with PKRhigh/p-AMPKpositive, and ADC patients with PKRhigh/p-AMPKnegative (B-D). Immunohistochemical staining examples for the expressions of PKR and p-AMPK in the cytoplasm of NSCLC cells (original magnification x400) (E).