Lipid metabolism reprogramming in renal cell carcinoma

Heravi, Gioia; Yazdanpanah, Omid; Podgorski, Izabela; Matherly, Larry H.; W, Liu

doi:10.1007/s10555-021-09996-w

Cited by 51 publications

(58 citation statements)

References 131 publications

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“…Finally, glutamine goes through reductive carboxylation to form citrate and support fatty acid production, particularly in VHL-deficient RCC when HIF-2α is overexpressed ( 24 ). Changes in fatty acid (FA) metabolism have been documented in ccRCC and accumulation of lipid droplets in the cytosol is a phenotypic characteristic of these tumors ( 34 ). For example, it has been shown that HIF-α represses the expression of carnitine palmitoyltransferase 1A (CPT1A) responsible for β-oxidation in the mitochondria ( 35 ).…”

Section: Introductionmentioning

confidence: 99%

Decrease of Intracellular Glutamine by STF-62247 Results in the Accumulation of Lipid Droplets in von Hippel-Lindau Deficient Cells

et al. 2022

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Kidney cancer is one of the top ten cancer diagnosed worldwide and its incidence has increased the last 20 years. Clear Cell Renal Cell Carcinoma (ccRCC) are characterized by mutations that inactivate the von Hippel-Lindau (VHL) tumor suppressor gene and evidence indicated alterations in metabolic pathways, particularly in glutamine metabolism. We previously identified a small molecule, STF-62247, which target VHL-deficient renal tumors by affecting late-stages of autophagy and lysosomal signaling. In this study, we investigated ccRCC metabolism in VHL-deficient and proficient cells exposed to the small molecule. Metabolomics profiling using 1H NMR demonstrated that STF-62247 increases levels of glucose, pyruvate, glycerol 3-phosphate while glutamate, asparagine, and glutathione significantly decreased. Diminution of glutamate and glutamine was further investigated using mass spectrometry, western blot analyses, enzymatic activities, and viability assays. We found that expression of SLC1A5 increases in VHL-deficient cells treated with STF-62247, possibly to stimulate glutamine uptake intracellularly to counteract the diminution of this amino acid. However, exogenous addition of glutamine was not able to rescue cell viability induced by the small molecule. Instead, our results showed that VHL-deficient cells utilize glutamine to produce fatty acid in response to STF-62247. Surprisingly, this occurs through oxidative phosphorylation in STF-treated cells while control cells use reductive carboxylation to sustain lipogenesis. We also demonstrated that STF-62247 stimulated expression of stearoyl-CoA desaturase (SCD1) and peripilin2 (PLIN2) to generate accumulation of lipid droplets in VHL-deficient cells. Moreover, the carnitine palmitoyltransferase 1A (CPT1A), which control the entry of fatty acid into mitochondria for β-oxidation, also increased in response to STF-62247. CPT1A overexpression in ccRCC is known to limit tumor growth. Together, our results demonstrated that STF-62247 modulates cellular metabolism of glutamine, an amino acid involved in the autophagy-lysosome process, to support lipogenesis, which could be implicated in the signaling driving to cell death.

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Section: Introductionmentioning

confidence: 99%

Decrease of Intracellular Glutamine by STF-62247 Results in the Accumulation of Lipid Droplets in von Hippel-Lindau Deficient Cells

et al. 2022

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“…Although the metabolic changes of the low dose group (ANL, 3 mg/kg) were not found, some metabolites, such as 5-HETE, DHA, and 19,20-EpDPA, were significantly decreased compared with those of the saline group (Figure 5). The tumor microenvironment and metabolism of RCC are receiving increasing attention (8,(29)(30)(31)(32). By analyzing 46 snap-frozen primary renal cell carcinomas and their corresponding normal renal cortex biopsies, the 5-LOX protein levels and metabolites of 5-HETE were found to be significantly elevated in RCC (33).…”

Section: Discussionmentioning

confidence: 99%

Serum Eicosanoids Metabolomics Profile in a Mouse Model of Renal Cell Carcinoma: Predicting the Antitumor Efficacy of Anlotinib

Xuan

et al. 2022

Front. Immunol.

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Anlotinib (ANL) shows promising efficacy in patients with renal cell cancer (RCC). Here, for the first time, a serum eicosanoid metabolomics profile and pharmacodynamics in Renca syngeneic mice treated with ANL was performed and integrated using our previous HPLC-MS/MS method and multivariate statistical analysis. The tumor growth inhibition rates of ANL were 39% and 52% at low (3 mg/kg) and high (6 mg/kg) dose levels, without obvious toxicity. A total of 15 disturbed metabolites were observed between the normal group and the model group, and the intrinsic metabolic phenotype alterations had occurred due to the treatment of ANL. A total of eight potential metabolites from the refined partial least squares (PLS) model were considered as potential predictive biomarkers for the efficacy of ANL, and the DHA held the most outstanding sensitivity and specificity with an area under the receiver operating characteristic curve of 0.88. Collectively, the results of this exploratory study not only provide a powerful reference for understanding eicosanoid metabolic reprogramming of ANL but also offer an innovative perspective for the development of therapeutic targets and strategies, the discovery of predictive biomarkers, and the determination of effective tumor monitoring approaches.

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“…Finally, diet T11 (diet T2 with 5% lipids) was better than diet T2 (14% lipids), while diet T12 (diet T2 with 25% lipids) was worse than diet T2 (see Table 4 and Figure 8). Lipid metabolic reprogramming and lipid accumulation are hallmarks of clear cell renal cell carcinoma [36,37,61]. Reducing the lipid content of our diets may therefore be important to increase their anticancer activity.…”

Section: Discussionmentioning

confidence: 99%

“…For example, the activity of diet T2 can be increased or decreased by changing the percentage of lipids (Figure 8). Since lipids are necessary for cancer development and survival [37,65], reducing lipid levels may have an additive and independent anticancer effect on the anticancer activity achieved by manipulating AAs. However, the anticancer activity of lipid restriction may also depend on restriction of specific AAs.…”

Section: Discussionmentioning

confidence: 99%

“…Since lipid metabolism plays a key role in renal cell carcinoma [36,37], we also evaluated the anticancer activity of two T2-derived diets in which lipid levels were reduced to 5% (diet T11) or increased to 25% (diet T12); diet T2 has 14% lipids (Table 2). Diet T11 was better than diet T2, and diet T12 was worse than diet T2, indicating that the reduction in lipid levels can increase the anticancer activity of the artificial diets (Table 4 and Figure 8b).…”

Section: Screening For In Vivo Anticancer Activity Of 10 Diets Based ...mentioning

confidence: 99%

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Manipulation of Amino Acid Levels With Artificial Diets Induces Anticancer Activity in Mice With Renal Cell Carcinoma

Calderón-Montaño¹,

Guillén-Mancina²,

Jiménez-Alonso³

et al. 2022

Preprint

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Targeted therapies with antiangiogenic drugs (e.g., sunitinib) and immune checkpoint inhibitors (e.g., anti-PD-1 antibodies) are the standard of care for patients with metastatic renal cell carcinoma. Although these treatments improve patient survival, they are rarely curative. We previously hypothesized that advanced cancers might be treated without drugs by using artificial diets in which the levels of specific amino acids (AAs) are manipulated. In this work, after showing that AA manipulation induces selective anticancer activity in renal cell carcinoma cells in vitro, we evaluated the anticancer activity of 17 artificial diets in a challenging animal model of renal cell carcinoma. The model was stablished by injecting murine renal cell carcinoma (Renca) cells into the peritoneum of immunocompetent BALB/cAnNRj mice. Mice survival was markedly improved when their normal diet was replaced with our artificial diets. Mice fed a diet lacking six AAs (diet T2) lived longer than mice treated with sunitinib or anti-PD-1 immunotherapy; several animals lived very long or were cured. Controlling the levels of several AAs (e.g., cysteine, methionine and leucine) and lipids was important for the anticancer activity of the diets. Additional studies are needed to further evaluate the therapeutic potential of this simple and inexpensive anticancer strategy.

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Lipid metabolism reprogramming in renal cell carcinoma

Cited by 51 publications

References 131 publications

Decrease of Intracellular Glutamine by STF-62247 Results in the Accumulation of Lipid Droplets in von Hippel-Lindau Deficient Cells

Decrease of Intracellular Glutamine by STF-62247 Results in the Accumulation of Lipid Droplets in von Hippel-Lindau Deficient Cells

Serum Eicosanoids Metabolomics Profile in a Mouse Model of Renal Cell Carcinoma: Predicting the Antitumor Efficacy of Anlotinib

Manipulation of Amino Acid Levels With Artificial Diets Induces Anticancer Activity in Mice With Renal Cell Carcinoma

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