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.
Highlights
Dysregulation of cellular energy metabolism, known as the Warburg effect, is closely linked to cancer development and progression
As we have previously demonstrated that glucose restriction (GR) combined with calorie restriction (CR)-mimetic plant-derived polyphenols has synergistic anticancer effects in malignant tumors [12], we investigated the anti-cancer effects of GR or curcumin treatments, and especially combination treatment in terms of intracellular pH regulation in human hepatoma cell lines because glucose metabolism is closely linked to cytosolic pH regulation
Because glycolysis is closely linked to the cytosolic pH and export of H+ ions, whether curcumin and/or GR affect the pHi was investigated in the hepatoma cell lines HepG2, Hep3B, and SNU449
Summary
Dysregulation of cellular energy metabolism, known as the Warburg effect, is closely linked to cancer development and progression. Alterations in proton dynamics have emerged as an important factor contributing to the etiopathogenesis of cancer cells, and energy dysregulation is thought to be attributable to increased intracellular pH (pHi) [2]. Intracellular alkalinization and extracellular acidification are commonly observed in malignant tumor tissues. This occurs as a result of the export of excess intracellular lactate and protons into the extracellular space by the transmembrane monocarboxylate transporter-4 (MCT4), coupled with the secretion of protons by Na+/H+ exchanger-1 (NHE1) or proton-extruding enzymes, including vacuolar H+-ATPase (v-ATPase) and carbonic anhydrases. Intracellular alkalinization has important biological effects, and even small changes in the pHi significantly affect protein activities. Inhibition of intracellular alkalinization is a potential anticancer approach, and various NHE1 inhibitors, such as cariporide, are under investigation [7]
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