Association between phosphorylated AMP-activated protein kinase and acetyl-CoA carboxylase expression and outcome in patients with squamous cell carcinoma of the head and neck.

Ying-Wen Su,Ruey-Kuen Hsieh,Yu-Chieh Lee,Yun-Ho Lin,Man-Hui Pai,Johnson Lin,I-Chih Fang,An-Chi Lo,Chi-Long Chen,Yi-Fang Chang,Pankaj K Singh

doi:10.1371/journal.pone.0096183

Abstract

BackgroundEpidemiological studies have indicated that impaired glucose metabolism may increase the risk of squamous cell carcinoma of the head and neck (SCCHN). AMP-activated protein kinase (AMPK) regulates glucose and lipid metabolism via the phosphorylation and subsequent inactivation of its downstream target acetyl-CoA carboxylase (ACC).Thus, we analyzed the expression of pAMPK and its downstream target phosphorylated acetyl-CoA carboxylase (pACC), as well as their impact on the survival of patients with resected SCCHN.MethodsOne hundred eighteen patients with surgically resected SCCHN were enrolled. Immunohistochemical (IHC) staining for pAMPK and pACC was performed using tissue microarrays of operative specimens of SCCHN. The expression was divided into two or three groups according to the IHC score [pAMPK: negative (0), positive (1–3); pACC: negative (0), low expression (1, 2), and high expression (3)]. Statistical analysis was performed to determine the association of pAMPK expression with clinicopathological features and pACC and pErk expression.ResultsThe positive rates of pAMPK and pACC expression were 64.4% (76/118) and 68.6% (81/118), respectively. pAMPK was significantly higher in patients aged younger than 60 years (P = 0.024; χ2test) and those with early-stage (T1/T2; P = 0.02; χ2 test) and oral cavity (P = 0.026; Fisher’s exact test) tumors. In multivariate analysis, pAMPK expression was not significantly correlated with overall survival (OS) (adjusted hazard ratio [HR]: 0.66; 95% confidence interval [CI]: 0.35–1.23), whereas high pACC expression was independently associated with worse OS in node-positive patients (adjusted HR: 17.58; 95% CI: 3.50–88.18).ConclusionsStrong expression of pACC was found to be an independent prognostic marker for patients with node-positive SCCHN. Our results suggest that pACC may play a role in tumor progression of SCCHN and may help to identify patient subgroups at high risk for poor disease outcome.

Highlights

Squamous cell carcinoma of the head and neck (SCCHN) is the seventh leading cause of cancer death worldwide [1]
Research Database [18], our SCHHN patients were predominantly male (92.4%) (Table 1). phosphorylated AMPK (pAMPK) and phosphorylated acetyl-CoA carboxylase (pACC) were found mainly in the cytoplasm of primary human tumor specimens, while normal mucosa tissues were negative or weakly stained in the nuclei (Fig. S1)
Because positive pAMPK expression was associated with early-stage (T1/ T2) tumor status and oral cavity tumors, we examined the prognostic significance of pAMPK in this patient subgroup

Summary

Introduction

Squamous cell carcinoma of the head and neck (SCCHN) is the seventh leading cause of cancer death worldwide [1]. Phosphorylation and activation of AMPK stimulates fatty acid oxidation through the phosphorylation and subsequent inhibition of its downstream target acetyl-CoA carboxylase (ACC). This leads to ATP generation and inhibition of ATP-consuming events, such as fatty acid synthesis [9]. Epidemiological studies have indicated that impaired glucose metabolism may increase the risk of squamous cell carcinoma of the head and neck (SCCHN). AMP-activated protein kinase (AMPK) regulates glucose and lipid metabolism via the phosphorylation and subsequent inactivation of its downstream target acetyl-CoA carboxylase (ACC).we analyzed the expression of pAMPK and its downstream target phosphorylated acetyl-CoA carboxylase (pACC), as well as their impact on the survival of patients with resected SCCHN

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