Metabolic interplay between glycolysis and mitochondrial oxidation: The reverse Warburg effect and its therapeutic implication

Lee, Minjong

doi:10.4331/wjbc.v6.i3.148

Cited by 122 publications

(123 citation statements)

References 191 publications

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“…Cancer cells preferentially utilize glycolytic metabolism to produce ATP, even in the presence of oxygen, a phenomenon termed aerobic glycolysis (6,7). Inhibition of glycolysis has been suggested to improve the outcomes for cancer therapy (8,9).…”

Section: Introductionmentioning

confidence: 99%

MicroRNA-18b inhibits the growth of malignant melanoma via inhibition of HIF-1α-mediated glycolysis

et al. 2016

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Abstract. MicroRNAs (miRs) have been demonstrated to play critical roles in the development and progression of malignant melanoma (MM). However, the exact role and underlying mechanism of miR-18b in MM growth remains unclear. In the present study, real-time PCR data indicated that miR-18b was significantly downregulated in MM tissues compared to their matched adjacent non-tumor tissues. Low miR-18b expression was significantly associated with the tumor thickness and stage, although no significant association was observed between the miR-18b expression and the age, gender, or lymph node metastasis. Besides, miR-18b was also significantly downregulated in MM B16 and A375 cells compared to normal skin HACAT cells. Ectopic expression of miR-18b decreased the proliferation of A375 and B16 cells, while induced a remarkable cell cycle arrest at G1 stage. Besides, miR-18b overexpression also inhibited the glycolysis in A375 and B16 cells. HIF-1α, a key regulator in glycolysis, was then identified as a target gene of miR-18b, and its expression was negatively mediated by miR-18b in A375 and B16 cells. Overexpression of HIF-1α rescued the suppressive effect of miR-18b on MM cell proliferation and glycolysis. In vivo study further showed that overexpression of miR-18b inhibited the MM growth as well as the tumor-related death, accompanied with HIF-1α downregulation. Taken together, the present study suggests that miR-18b inhibits the growth of MM cells in vitro and in vivo through directly targeting HIF-1α.

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Section: Introductionmentioning

confidence: 99%

MicroRNA-18b inhibits the growth of malignant melanoma via inhibition of HIF-1α-mediated glycolysis

et al. 2016

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“…Understanding of this aberrant phenomenon of aerobic glycolysis in cancer cells has led to novel tumor therapeutic strategies targeted at switching back to mitochondrial oxidative phosphorylation and there by leading to cancer cell death [26]. Several compounds have been reported to suppress the growth of tumor cells by affecting aerobic glycolysis [26].…”

Section: Discussionmentioning

confidence: 99%

“…Several compounds have been reported to suppress the growth of tumor cells by affecting aerobic glycolysis [26]. Three key rate limiting enzymes in aerobic glycolysis are: hexokinase, pyruvate kinase (PK) and lactate dehydrogenase (LDH) [20].…”

Section: Discussionmentioning

confidence: 99%

Oleanolic Acid Inhibits High Salt-Induced Exaggeration of Warburg-like Metabolism in Breast Cancer Cells

Amara

Zheng

Tiriveedhi

2016

Cell Biochem Biophys

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Cancer cells have a proliferative advantage by utilizing intermediates of aerobic glycolysis (Warburg-effect) for their macromolecule synthesis. Although the exact causes of this Warburg-effect are unclear, high osmotic stress in solid tumor microenvironment is considered as one of the important factors. Oleanolic acid (OA) is known to exert anti-inflammatory and anti-cancer effect. In our current studies, using breast cancer cell lines, we determined the protective role of OA in high salt mediated osmotic stress induced cancer growth. Hypertonic (0.16M NaCl) culture conditions enhanced the cancer cell growth (26%, p<0.05) and aerobic glycolysis as marked by increased glucose consumption (34%, p<0.05) and lactate production (25%, p<0.05) over untreated cells. This effect was associated with increased expression and activity of key rate-limiting enzymes of aerobic glycolysis, namely, hexokinase, pyruvate kinase-typeM2 and lactate dehydrogenase-A. Interestingly, this high salt mediated enhanced expression of aerobic glycolytic enzymes was efficiently reversed by OA along with decreased cancer cell proliferation. In cancer cells, enhanced aerobic glycolysis is associated with decreased mitochondrial activity and mitochondrial-associated caspase activity. As expected, high salt further inhibited the mitochondrial related cytochrome oxidase and caspase-3 activity. However, OA efficiently reversed the high salt mediated inhibition of cytochrome oxidase, caspase activity and pro-apoptotic Bax expression, thus suggesting that OA induced mitochondrial activity and enhanced apoptosis. Taken together, our data indicate that OA efficiently reverses the enhanced Warburg-like metabolism induced by high salt mediated osmotic stress along with potential application of OA in anti-cancer therapy.

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“…Yoshida, in 2015, showed that tumours expressing high levels of MCT4 do no exhibit the reverse Warburg effect [55]. The microenvironment of cancer is ever changing, and cancer cells can and do vary in their metabolic phenotype even within the same tumour mass [56]. Although hard to generalise in solid tumours with a hypoxic core, perhaps the Warburg effect most probably predominates with reduced oxygen levels driving the cells to make the most of all available glucose.…”

Section: Positron Emission Tomography Imaging and The Reverse Warburgmentioning

confidence: 99%

The Warburg effect: 80 years on

Potter

Newport

Morten

2016

Biochemical Society Transactions

388

343

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Influential research by Warburg and Cori in the 1920s ignited interest in how cancer cells' energy generation is different from that of normal cells. They observed high glucose consumption and large amounts of lactate excretion from cancer cells compared with normal cells, which oxidised glucose using mitochondria. It was therefore assumed that cancer cells were generating energy using glycolysis rather than mitochondrial oxidative phosphorylation, and that the mitochondria were dysfunctional. Advances in research techniques since then have shown the mitochondria in cancer cells to be functional across a range of tumour types. However, different tumour populations have different bioenergetic alterations in order to meet their high energy requirement; the Warburg effect is not consistent across all cancer types. This review will discuss the metabolic reprogramming of cancer, possible explanations for the high glucose consumption in cancer cells observed by Warburg, and suggest key experimental practices we should consider when studying the metabolism of cancer.

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Metabolic interplay between glycolysis and mitochondrial oxidation: The reverse Warburg effect and its therapeutic implication

Cited by 122 publications

References 191 publications

MicroRNA-18b inhibits the growth of malignant melanoma via inhibition of HIF-1α-mediated glycolysis

MicroRNA-18b inhibits the growth of malignant melanoma via inhibition of HIF-1α-mediated glycolysis

Oleanolic Acid Inhibits High Salt-Induced Exaggeration of Warburg-like Metabolism in Breast Cancer Cells

The Warburg effect: 80 years on

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