title: MACC1 supports human gastric cancer growth under metabolic stress by enhancing the Warburg effect.
abstract: Cancer cells mainly metabolize by glycolysis (the Warburg effect) and are better adapted to resist metabolic stress. Metastasis-associated in colon cancer-1 (MACC1) is an oncogene promoting gastric cancer (GC) growth and metastasis, and its expression positively correlates with GC progression. However, it is unknown why MACC1 elevates with GC progression and what is its role in cancer metabolism. In this study, we discovered that MACC1 expression was significantly upregulated via adenosine monophosphate-activated protein kinase signaling in response to glucose deprivation-induced metabolic stress. Clinical observation demonstrates that MACC1 expression was higher in advanced stage GC. MACC1 expression was proved to be positively correlated with the maximum standardized uptake value of (18)F-deoxyglucose in the patients, and MACC1 enhanced (18)F-deoxyglucose uptake in GC cells and the xenografts. The underlying mechanism was that MACC1 promoted the Warburg effect by upregulating the activities and expressions of a series of glycolytic enzymes, including hexokinase, pyruvate dehydrogenase kinase and lactate dehydrogenase, in GC cells. This metabolic shift enhanced cell viability and resistance to apoptosis by facilitating ATP generation, reducing the reactive oxygen species production and stabilizing the mitochondrial membrane potential. In contrast, MACC1-silenced or the Warburg effect-blocked GC cells were more vulnerable to metabolic stress. In conclusion, metabolic stress is one of the mechanisms that elevate MACC1 expression in GC, and MACC1 upregulation compensatively ensures GC growth against metabolic stress by facilitating the Warburg effect.
authors.affiliation: Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
authors.forename: L
authors.initials: L
authors.lastname: Lin
authors.affiliation: Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
authors.forename: H
authors.initials: H
authors.lastname: Huang
authors.affiliation: Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
authors.forename: W
authors.initials: W
authors.lastname: Liao
authors.affiliation: Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
authors.forename: H
authors.initials: H
authors.lastname: Ma
authors.affiliation: Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
authors.forename: J
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
authors.forename: L
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
authors.forename: N
authors.initials: N
authors.lastname: Huang
authors.affiliation: Department of Cardiology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Liao
authors.affiliation: Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
authors.forename: W
authors.initials: W
authors.lastname: Liao
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics*; D002470:Cell Survival / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006019:Glycolysis / Q000235:genetics; D006801:Humans; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000235:genetics; D008875:Middle Aged; D008928:Mitochondria / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D013274:Stomach Neoplasms / Q000235:genetics*; D013312:Stress, Physiological / Q000235:genetics*; D015534:Trans-Activators; D014157:Transcription Factors / Q000235:genetics*; D015854:Up-Regulation / Q000235:genetics; D058494:Walker-Warburg Syndrome / Q000235:genetics*
chemical_list: C544162:MACC1 protein, human; D017382:Reactive Oxygen Species; D015534:Trans-Activators; D014157:Transcription Factors