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Curcumin Treatment in Combination with Glucose Restriction Inhibits Intracellular Alkalinization and Tumor Growth in Hepatoma Cells

 So Won Kim  ;  Min-Ji Cha  ;  Seul-Ki Lee  ;  Byeong-Wook Song  ;  Xinghai Jin  ;  Jae Myun Lee  ;  Jeon Han Park  ;  Jong Doo Lee 
 International Journal of Molecular Sciences, Vol.20(10) : E2375, 2019 
Journal Title
 International Journal of Molecular Sciences 
Issue Date
Alkalies/metabolism ; Antineoplastic Agents/pharmacology* ; Carcinoma, Hepatocellular/metabolism* ; Cell Line ; Cell Proliferation/drug effects ; Curcumin/pharmacology* ; Glucose/deficiency* ; Glucose/metabolism ; Hep G2 Cells ; Humans ; Liver Neoplasms/metabolism* ; Monocarboxylic Acid Transporters/metabolism ; Regulatory-Associated Protein of mTOR/metabolism ; Vacuolar Proton-Translocating ATPases/metabolism
curcumin ; glucose restriction ; hepatoma ; intracellular pH ; tumor suppression
Dysregulation of cellular energy metabolism is closely linked to cancer development and progression. Calorie or glucose restriction (CR or GR) inhibits energy-dependent pathways, including IGF-1/PI3K/Akt/mTOR, in cancer cells. However, alterations in proton dynamics and reversal of the pH gradient across the cell membrane, which results in intracellular alkalinization and extracellular acidification in cancer tissues, have emerged as important etiopathogenic factors. We measured glucose, lactate, and ATP production after GR, plant-derived CR-mimetic curcumin treatment, and curcumin plus GR in human hepatoma cells. Intracellular pH regulatory effects, in particular, protein-protein interactions within mTOR complex-1 and its structural change, were investigated. Curcumin treatment or GR mildly inhibited Na+/H+ exchanger-1 (NHE1). vATPase, monocarboxylate transporter (MCT)-1, and MCT4 level. Combination treatment with curcumin and GR further enhanced the inhibitory effects on these transporters and proton-extruding enzymes, with intracellular pH reduction. ATP and lactate production decreased according to pH change. Modeling of mTOR protein revealed structural changes upon treatments, and curcumin plus GR decreased binding of Raptor and GβL to mTOR, as well as of Rag A and Rag B to Raptor. Consequently, 4EBP1 phosphorylation was decreased and cell migration and proliferation were inhibited in a pH-dependent manner. Autophagy was increased by curcumin plus GR. In conclusion, curcumin treatment combined with GR may be a useful supportive approach for preventing intracellular alkalinization and cancer progression.
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1. College of Medicine (의과대학) > Dept. of Microbiology (미생물학교실) > 1. Journal Papers
Yonsei Authors
Park, Jeon Han(박전한) ORCID logo https://orcid.org/0000-0001-9604-3205
Lee, Jae Myun(이재면) ORCID logo https://orcid.org/0000-0002-5273-3113
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