AMPK-mediated energy homeostasis and associated metabolic effects on cancer cell response and resistance to cetuximab
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Xinqun Li1, Yang Lu1, Haiquan Lu1, Jingtao Luo1,2, Yun Hong1,3, Zhen Fan1
1Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
2Department of Head and Neck Oncology, Tianjin Medical University Cancer Institute & Hospital, Tianjin, China
3Department of Oral Medicine, Guanghua School of Stomatology, Sun Yat-Sen University, Guangzhou, Guangdong, China
Zhen Fan, e-mail: [email protected]
Keywords: EGFR, cetuximab, HIF-1, AMPK, cancer metabolism
Received: January 21, 2015 Accepted: February 23, 2015 Published: March 20, 2015
We previously reported that cetuximab, an EGFR-blocking antibody, inhibits cancer metabolism via downregulation of HIF-1α and reverses the Warburg effect in cancer cells. Here, we report that inhibition of HIF-1 transcriptional activity by cetuximab does not necessarily lead to successful inhibition of cell proliferation. In several head and neck squamous cell carcinoma (HNSCC) cell lines, we observed a pattern of oscillating decrease and increase of intracellular ATP level after cetuximab treatment, and the magnitude and kinetics of which varied by cell line and appeared to be linked to the extent of cellular response to cetuximab. In HNSCC cells with low basal level of AMPK activity and that responded to cetuximab-induced growth inhibition, there was a transient, LKB1-dependent activation of AMPK. In contrast, HNSCC cells that had a high basal level of AMPK activity were less sensitive to cetuximab-induced growth inhibition despite effective inhibition of EGFR downstream signaling by cetuximab. Knockdown or inhibition of AMPK markedly enhanced response to cetuximab via induction of apoptosis. These findings indicate that a transient activation of AMPK is an early metabolic marker of cellular response to cetuximab and that high and sustained AMPK activity is an important mechanism by which cancer cells survive cetuximab treatment.
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