ARCA Cy3 EGFP br Introduction Initial studies of cancer meta

Introduction Initial studies of cancer metabolism in the early 1920s showed that the cancer phenotype for glucose metabolism is unique, with increased abilities to take up glucose and produce lactate, even under aerobic conditions [1]. This pathway, called aerobic glycolysis or the Warburg effect, results in extracellular fluid around tumor tissue having acidic pH [1], [2]. Indeed, the extracellular pH (pH) of most tumor tissues is around 6.5–6.9, and may be even lower (e.g., 5.7) in some cases [3], [4], [5]. However, despite lactate production by tumor tissue, blood lactate level is often unaffected [6], suggesting that acidity is limited locally to the microenvironment around tumor tissue. Accumulated evidence about cancer phenotypes has indicated that all cancers have in common six biological capabilities acquired during multistep development: sustained proliferative signaling, evasion of growth suppressors, resistance to cell death, replicative immortality, induction of angiogenesis, and activation of invasion and metastasis [7]. Later research has revealed two additional hallmarks of cancer: reprogrammed energy metabolism and evasion of immune-mediated destruction [8]. Recent studies have shown that metabolic reprogramming regulates cancer stemness [9]. Thus, “cancer metabolism” has again become an important research topic. Here, we focus on glucose and glutamine metabolism.
Glucose metabolism and its regulation
Acidic metabolites
Hyaluronidases and cathepsins have optimal activity at acidic pH, allowing their efficient ARCA Cy3 EGFP of extracellular matrices in an acidic pH microenvironment [121], [122], [123]. Acidic pH also affects cellular activity through an as yet incompletely identified intracellular signaling cascade. Acid sensing ion channel 1a (ASIC1a) is an H+ gated cation channel. Its activation by acidic pH results in Ca2+ influx, thereby activating calmodulin-dependent protein kinase II [124]. Ca2+ influx through ASIC1a also activates PI3K/AKT signaling, which has been associated with resistant to anticancer drugs [125]. PI3K/AKT signaling, in turn, activates mTOR, which has been associated with various diseases, including cancers [126]. We have reported that acidic pH-triggered Ca2+ influx activates phospholipase D (PLD); two mitogen activated kinases (MAPKs), p38 and extracellular signal-regulated kinase 1/2 (ERK1/2); and the NF-κB pathway, resulting in the induction of matrix metalloproteinase-9 (MMP-9) expression [127], [128], [129] (Fig. 4). The MMP-9 induction rate was found to correlate with cellular metastatic activity in mouse B16 melanoma cells. Acidic pH-induced activation of MAPKs (p38 and ERK1/2) and NF-κB is common in mice and humans [130], [131]. Moreover, acidic pH also stimulated acidic sphingomyelinase activity, the activation of which is independent of intracellular Ca2+, as well as contributing to NF-κB activation [132]. Acidic pH signaling was recently shown to upregulate the expression of PLD isozyme type 1 (PLD1), but not type 2 (PLD2) via activation of rhoA [133]. Phosphatidate, which is a PLD product, was reported to show survival signaling by activating mTOR and inhibiting MDM2, the ubiquitin ligase of p53 [134], [135]. We found that acidic pH changes the morphology of cancer cells to fibroblastic, as shown by the induction of matrigel invasion; up-regulation of MMP-9, vimentin, MMP-3, and MMP-13 gene expression; and down-regulation of E-cadherin expression [127], [136]. These findings indicated that acidic pH induces epithelial mesenchymal transition (EMT), an important event in the development of a metastatic phenotype [136]. Similar, others have also reported that acidic pH induced EMT-like changes [130], [137]. Acidic pH may contribute to drug resistance through ASIC1a/Ca2+/PI3K/AKT/mTOR signaling. Moreover, drugs that inhibit this signaling may have efficacy in suppressing acidic pH −mediated malignant phenotype. Antitumor drugs that inhibit the PI3K/AKT/mTOR pathway are currently being tested in clinical trials, with some, such as BEZ235, approved for treatment [138]. These drugs are expected to effectively suppress the acidic pH-associated malignant phenotype of human cancer cells.