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

1
Department of Pharmacology, Catholic Kwandong University College of Medicine, Gangneung 25601, Korea
2
Institute for Translational and Clinical Research, Catholic Kwandong University International St. Mary’s Hospital, Incheon 22711, Korea
3
KANT Science Research Institute, Incheon 22711, Korea
4
Department of Medical Science, Catholic Kwandong University College of Medicine, Gangneung 25601, Korea
5
Brain Korea 21 PLUS Project for Medical Sciences, Yonsei University College of Medicine, Seoul 03722, Korea
6
Department of Microbiology and Immunology, Institute for Immunology and Immunological Diseases, Yonsei University College of Medicine, Seoul 03722, Korea
7
Department of Nuclear Medicine, Catholic Kwandong University International St. Mary’s Hospital, Incheon 22711, Korea
*
Authors to whom correspondence should be addressed.
These authors contributed equally to this work.
Int. J. Mol. Sci. 2019, 20(10), 2375; https://doi.org/10.3390/ijms20102375
Received: 18 April 2019 / Revised: 9 May 2019 / Accepted: 11 May 2019 / Published: 14 May 2019
(This article belongs to the Special Issue Health Promoting Effects of Phytochemicals)
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Abstract

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. View Full-Text
Keywords: hepatoma; intracellular pH; curcumin; glucose restriction; tumor suppression hepatoma; intracellular pH; curcumin; glucose restriction; tumor suppression
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    Description: Supplementary Figure 1. pHi-lowering effect of curcumin and glucose restriction in the human hepatoma cell lines HepG2, Hep3B, and SNU449. experiment was conducted five times independently. Con, standard RPMI-1640 medium; Cur, curcumin; GR, glucose restriction, 5.5 mM glucose medium; GR Cur, glucose restriction plus curcumin. *p<0.05 vs control; **p<0.01 vs control Supplementary Figure 2. Effect of curcumin and glucose restriction on the pHi in HDFa human dermal fibroblasts. The pHi is within the normal range, even after curcumin treatment under glucose restriction condition. experiment was conducted five times independently. Con, standard RPMI-1640 medium; Cur, curcumin; Car, cariporide; PMA, phorbol-12-myristate-13-acetate; GR, glucose restriction, 5.5 mM glucose medium; GR Cur, glucose restriction plus curcumin Supplementary Figure 3. NHE1 mRNA level affected by curcumin, cariporide, PMA, and glucose restriction conditions. NHE1 mRNA level was detected by (A, B) RT-PCR and (C) qRT-PCR. The experiment was conducted three times independently. Con, standard RPMI-1640 medium; Cur, curcumin; Car, cariporide; PMA, phorbol-12-myristate-13-acetate; GR, glucose restriction, 5.5 mM glucose medium; GR Cur, glucose restriction plus curcumin. *p<0.05 vs control; *****p<0.0005 vs control; +p<0.05 vs GR Supplementary Figure 4. Effect of curcumin and glucose restriction on ATP production in (A) Hep3B, (B) SNU449, (C) HEMa, and (D) HDFa cells. Confocal ATP images were taken after 30-min treatment of human melanocytes with curcumin under low-glucose condition (magnification, 400). Con, standard RPMI-1640 medium; GR Cur, glucose restriction plus curcumin Supplementary Figure 5. Confocal imaging of autophagosomes of (A) HepG3B and (B) HDFa cells. Cells were immunostained with an LC3 antibody. Con, standard RPMI-1640 medium; GR Cur, glucose restriction plus curcumin
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Kim, S.W.; Cha, M.-J.; Lee, S.-K.; Song, B.-W.; Jin, X.; Lee, J.M.; Park, J.H.; Lee, J.D. Curcumin Treatment in Combination with Glucose Restriction Inhibits Intracellular Alkalinization and Tumor Growth in Hepatoma Cells. Int. J. Mol. Sci. 2019, 20, 2375.

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