Oxamate-mediated inhibition of lactate dehydrogenase induces protective autophagy in gastric cancer cells: Involvement of the Akt–mTOR signaling pathway

Zhao, Zhengwei; Han, Fanghai; Yang, Shibin; Wu, Jianhai; Zhan, Wenbin

doi:10.1016/j.canlet.2014.11.046

Cited by 135 publications

(113 citation statements)

References 37 publications

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“…The well-known Warburg effect demonstrates that lactate would be highly produced by cancer cell through aerobic glycolysis even at normoxia condition [20]. Oxalic acid was the one of LDH inhibitor which converted pyruvate to lactate [21]. To verify whether lactate in cancer cell CM correlated with the Nrf2 activation of TEM, we reduced the lactate in cancer cell CM by pre-incubated the cancer cell with the oxalic acid containing media (Fig.…”

Section: Resultsmentioning

confidence: 99%

Nrf2 activation drive macrophages polarization and cancer cell epithelial-mesenchymal transition during interaction

et al. 2018

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BackgroundThe M2 phenotype of tumor-associated macrophages (TAM) inhibits the anti-tumor inflammation, increases angiogenesis and promotes tumor progression. The transcription factor Nuclear Factor (erythroid-derived 2)-Like 2 (Nrf2) not only modulates the angiogenesis but also plays the anti-inflammatory role through inhibiting pro-inflammatory cytokines expression; however, the role of Nrf2 in the cancer cell and macrophages interaction is not clear.MethodsHepatocellular carcinoma cells (Hep G2 and Huh 7) and pancreatic cancer cells (SUIT2 and Panc-1) were co-cultured with monocytes cells (THP-1) or peripheral blood monocytes derived macrophages, then the phenotype changes of macrophages and epithelial-mesenchymal transition of cancer cells were detected. Also, the role of Nrf2 in cancer cells and macrophages interaction were investigated.ResultsIn this study, we found that cancer cells could induce an M2-like macrophage characterized by up-regulation of CD163 and Arg1, and down-regulation of IL-1b and IL-6 through Nrf2 activation. Also, Nrf2 activation of macrophages promoted VEGF expression. The Nrf2 activation of macrophages correlated with the reactive oxygen species induced by cancer cells derived lactate. Cancer cells educated macrophages could activate Nrf2 of the cancer cells, in turn, to increase cancer cells epithelial-mesenchymal transition (EMT) through paracrine VEGF. These findings suggested that Nrf2 played the important role in the cancer cells and macrophages interaction.ConclusionsMacrophage Nrf2 activation by cancer cell-derived lactate skews macrophages polarization towards an M2-like phenotype and educated macrophages activate Nrf2 of the cancer cells to promote EMT of cancer cells. This study provides a new understanding of the role of Nrf2 in the cancer cell and TAM interaction and suggests a potential therapeutic target.Electronic supplementary materialThe online version of this article (10.1186/s12964-018-0262-x) contains supplementary material, which is available to authorized users.

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Section: Resultsmentioning

confidence: 99%

Nrf2 activation drive macrophages polarization and cancer cell epithelial-mesenchymal transition during interaction

et al. 2018

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“…So, autophagy has dual mechanism; cytoprotective role and death-prompting mechanism. Some regulators of protective autophagy are AMPK, mitogen activated protein kinase, Akt and mammalian target of rapamycin (Carchman et al 2013;Wang et al 2013;Zhao et al 2014;Jiang et al 2014).…”

Section: Discussionmentioning

confidence: 99%

Metformin improves anxiety-like behaviors through AMPK-dependent regulation of autophagy following transient forebrain ischemia

et al. 2015

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Stroke is one of the main threats to the public health worldwide. Metformin, an anti-diabetic drug, is an activator of AMP-activated protein kinase (AMPK). Metformin plays an important role on improving behavior in neurodegenerative diseases through diverse pathways. In the current study we aimed to investigate the probable effects of metformin on anxiety and autophagy pathway in global cerebral ischemia. Rats were divided into seven groups; Sham, ischemia (I/R), metformin (met), compound c (CC), CC+ischemia, met+ischemia, met+CC+ischemia. Metformin was pretreated for 2 weeks and CC administrated half an hour before global cerebral ischemia. Blood glucose, body weight, sensorimotor scores, elevated plus maze and open field test were evaluated after ischemia. Autophagy related factors were measured by Western blot and immunofluorescent assay in hippocampus of rats. Based on our results, pretreatment of rats by metformin improved sensory motor signs, anxiolytic behavior and locomotion in ischemic rats. CC injection in I/R rats attenuated the therapeutic effects of metformin. Autophagy factors such as light chain 3B, Atg7, Atg5-12 and beclin-1 decreased in ischemic rats compared to the sham group (P < 0.001 in all proteins). Level of autophagic factors increased in metformin pretreated rats compared to global cerebral ischemia (P < 0.001 in all proteins). These data indicated that the beneficial role of metformin in behavior and autophagy flux mediates via AMPK. Our results recommended that metformin therapy could improve psychological disorders and movement disability following I/R and profound understanding of AMPK-dependent autophagy would enhance its development as a promising target for intracellular pathway.

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“…Currently, surgical treatment is the main therapy of GC, although the outcome of the treatment is far from satisfaction [8][9][10][11]. Chemotherapy, especially fluorouracil (5-FU), is used as a supplementary treatment for GC and has resulted in better survival of the patients [12][13][14][15][16]. However, the molecular mechanisms underlying the anti-cancer effects of 5-FU are not completely understood.…”

Section: Introductionmentioning

confidence: 97%

Fluorouracil induces autophagy-related gastric carcinoma cell death through Beclin-1 upregulation by miR-30 suppression

Yang¹,

Pan²

2015

Tumor Biol.

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The molecular mechanisms underlying the anti-cancer effects of chemotherapy drugs are not completely understood. Here, we studied the effects of fluorouracil (5-FU) on gastric carcinoma (GC) cells. We found that 5-FU dose-dependently inhibited the growth of GC cells, in either a cell counting kit-8 (CCK-8) assay or a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Moreover, autophagy-associated protein 6 (ATG6) or Beclin-1 was dose-dependently activated by 5-FU in GC cells. Further, microRNA (miR)-30 was found to be regulated by 5-FU, and bioinformatics analysis showed that miR-30 targeted the 3'-UTR of Beclin-1 to inhibit its translation. Together, these data suggest that 5-FU may suppress miR-30 to upregulate Beclin-1 to induce autophagic cell death and cell proliferation arrest in GC cells.

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Oxamate-mediated inhibition of lactate dehydrogenase induces protective autophagy in gastric cancer cells: Involvement of the Akt–mTOR signaling pathway

Cited by 135 publications

References 37 publications

Nrf2 activation drive macrophages polarization and cancer cell epithelial-mesenchymal transition during interaction

Nrf2 activation drive macrophages polarization and cancer cell epithelial-mesenchymal transition during interaction

Metformin improves anxiety-like behaviors through AMPK-dependent regulation of autophagy following transient forebrain ischemia

Fluorouracil induces autophagy-related gastric carcinoma cell death through Beclin-1 upregulation by miR-30 suppression

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