Metabolic rewiring in melanoma

Ratnikov, Boris I.; Scott, David A.; Osterman, Andrei L.; Smith, Jeffrey W.; Ronai, Ze’ev

doi:10.1038/onc.2016.198

Cited by 141 publications

(154 citation statements)

References 133 publications

(180 reference statements)

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“…Our data support a model in which cells growing under PPSS become multidrug resistant due to rewiring of signaling pathways involved in the regulation of important proteins for chemoresistance (MDR1 and ABCG2) and survival (Bcl‐2). Rewiring of signaling networks has been demonstrated during oxidative stress (Garcia et al, ) as well as an adaptation mechanism to low nutrient and oxygen conditions (Ratnikov et al, ). We provide evidence that PPSS may induce or strengthen crosstalk between MDR1, ABCG2, and Bcl‐2 that are negligible or non‐existent in cells growing under RCC.…”

Section: Resultsmentioning

confidence: 99%

Chemoresistance of Lung and Breast Cancer Cells Growing Under Prolonged Periods of Serum Starvation

Yakisich

Venkatadri

Azad

et al. 2017

Journal Cellular Physiology

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The efficacy of chemotherapy is hindered by both tumor heterogeneity and acquired or intrinsic multi-drug resistance caused by the contribution of multidrug resistance proteins and stemness-associated prosurvival markers. Therefore, targeting multi-drug resistant cells would be much more effective against cancer. In this study, we characterized the chemoresistance properties of adherent (anchorage-dependent) lung H460 and breast MCF-7 cancer cells growing under prolonged periods of serum starvation (PPSS). We found that under PPSS, both cell lines were highly resistant to Paclitaxel, Colchicine, Hydroxyurea, Obatoclax, Wortmannin, and LY294002. Levels of several proteins associated with increased stemness such as Sox2, MDR1, ABCG2, and Bcl-2 were found to be elevated in H460 cells but not in MCF-7 cells. While pharmacological inhibition of either MDR1, ABCG2, Bcl-2 with Verapamil, Sorafenib, or Obatoclax, respectively decreased the levels of their target proteins under routine culture conditions as expected, such inhibition did not reverse PX resistance in PPSS conditions. Paradoxically, treatment with inhibitors in serum-starved conditions produced an elevation of their respective target proteins. In addition, we found that Digitoxin, an FDA approved drug that decrease the viability of cancer cells growing under PPSS, downregulates the expression of Sox2, MDR1, phospho- AKT, Wnt5a/b, and β-catenin. Our data suggest that PPSS-induced chemoresistance is the result of extensive rewiring of intracellular signaling networks and that multi-resistance can be effectively overcome by simultaneously targeting multiple targets of the rewired network. Furthermore, our PPSS model provides a simple and useful tool to screen drugs for their ability to target multiple pathways of cancer resistance. J. Cell. Physiol. 232: 2033-2043, 2017. © 2016 Wiley Periodicals, Inc.

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Section: Resultsmentioning

confidence: 99%

Chemoresistance of Lung and Breast Cancer Cells Growing Under Prolonged Periods of Serum Starvation

Yakisich

Venkatadri

Azad

et al. 2017

Journal Cellular Physiology

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“…Many previous studies have revealed that lactate might have serious effects on the tumor-infiltrating immune cells, and decrease their immune surveillance by various mechanisms [4,5].…”

Section: Original Papermentioning

confidence: 99%

Increased Lactate in Gastric Cancer Tumor-Infiltrating Lymphocytes Is Related to Impaired T Cell Function Due to miR-34a Deregulated Lactate Dehydrogenase A

Wang

Senyan

et al. 2018

Cell Physiol Biochem

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Background/Aims: Lactate is one of the products of glycolysis and is a hallmark of the Warburg effect. Glycolysis is found in tumor as well as immune cells. However, the effects of lactate on the function of tumor-infiltrating T cells (TILs) are rarely reported. Methods: In the present study, we investigated lactate and other glycolysis-related metabolites within TILs of human gastric cancer (GC). Lactate concentration was determined by liquid chromatography–mass spectrometry. The functional effects and clinical relevance of excessive lactate on T cells were investigated in clinical samples, and the mechanism of increased lactate was explored. Results: Lactate was significantly increased in GC TILs and related to decreased T helper (Th)1 cells and cytotoxic T lymphocytes (CTLs). Increased lactate within GC TILs was positively correlated with increased lactate dehydrogenase A (LDH)A. Expression of LDHA in GC TILs was also negatively correlated with percentages of Th1 cells and CTLs. Decreased miR-34a expression in GC TILs was responsible for increased expression of LDHA. A hypoxic tumor environment was responsible for decreased miR-34a and lactate-induced impaired immune function. Conclusion: We found that hypoxia decreases miR-34a expression and lose miR-34a regulation on LDHA, thus increasing lactate level within GC TILs and impairing immune function in GC.

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“…Although the Warburg effect is considered the basic feature of metabolic reprogramming, a large amount of evidence suggests that tumour cells rely on both mitochondrial metabolism and glycolysis . Previous studies have shown that BRAF V600E is involved in melanoma metabolic reprogramming . Haq et al .…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial metabolism is inhibited by the HIF1α‐MYC‐PGC‐1β axis in BRAF V600E thyroid cancer

Gao

Yang

et al. 2019

The FEBS Journal

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BRAF V600E is the most common mutation identified in thyroid cancers. However, the relationship between BRAF V600E and metabolic reprogramming in thyroid cancer is unclear. Here, we investigate the mechanism of metabolic reprogramming in BRAF V600E thyroid cancer by constructing BRAF V600E‐overexpressing and BRAF‐knockdown thyroid cell lines for use in mitochondrial respiration and glycolysis experiments. Western blot and RT‐qPCR were performed to measure the level of metabolism‐related proteins, and various approaches were used to investigate transcriptional regulation. In thyroid cancer cells, the overexpression of BRAF V600E inhibited OXPHOS gene expression and mitochondrial respiration but enhanced aerobic glycolysis. Clinical thyroid cancer samples carrying the BRAF V600E mutation had suppressed levels of PGC‐1β but increased expression of HIF1α. Our results show that BRAF V600E reduced mitochondrial respiration by decreasing the expression of PGC‐1β. In addition, HIF1α, which is a target of BRAF V600E, was found to regulate the expression of PGC‐1β via MYC. Furthermore, glycolysis‐related enzymes, such as LDHA and PKM2, were upregulated in BRAF V600E mutant thyroid cancer specimens, thereby promoting glycolysis. MEK1/2 inhibitor treatment enhanced the specific dependence of BRAF V600E mutant thyroid cancer on mitochondrial respiration. These results indicate that in thyroid cancer, the BRAF V600E mutation alters the HIF1α‐MYC‐PGC‐1β axis, causing mitochondrial respiration to be inhibited and aerobic glycolysis to be enhanced.

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Metabolic rewiring in melanoma

Cited by 141 publications

References 133 publications

Chemoresistance of Lung and Breast Cancer Cells Growing Under Prolonged Periods of Serum Starvation

Chemoresistance of Lung and Breast Cancer Cells Growing Under Prolonged Periods of Serum Starvation

Increased Lactate in Gastric Cancer Tumor-Infiltrating Lymphocytes Is Related to Impaired T Cell Function Due to miR-34a Deregulated Lactate Dehydrogenase A

Mitochondrial metabolism is inhibited by the HIF1α‐MYC‐PGC‐1β axis in BRAF V600E thyroid cancer

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