title: AMPK-mediated energy homeostasis and associated metabolic effects on cancer cell response and resistance to cetuximab.
abstract: 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.
authors: Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: Xinqun
authors: X
authors: Li
authors: Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: Yang
authors: Y
authors: Lu
authors: Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: Haiquan
authors: H
authors: Lu
authors: Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.|Department of Head and Neck Oncology, Tianjin Medical University Cancer Institute & Hospital, Tianjin, China.
authors: Jingtao
authors: J
authors: Luo
authors: Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.|Department of Oral Medicine, Guanghua School of Stomatology, Sun Yat-Sen University, Guangzhou, Guangdong, China.
authors: Yun
authors: Y
authors: Hong
authors: Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: Zhen
authors: Z
authors: Fan
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000255:Adenosine Triphosphate / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D000068818:Cetuximab / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D004734:Energy Metabolism / Q000187:drug effects*; D004789:Enzyme Activation; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D006706:Homeostasis; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D015398:Signal Transduction / Q000187:drug effects; D000077195:Squamous Cell Carcinoma of Head and Neck; D013997:Time Factors; D014162:Transfection
chemical_list: D000970:Antineoplastic Agents; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D047428:Protein Kinase Inhibitors; D000255:Adenosine Triphosphate; D017346:Protein Serine-Threonine Kinases; C109790:STK11 protein, human; D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases; D000068818:Cetuximab
keywords: AMPK; EGFR; HIF-1; cancer metabolism; cetuximab