Renal Lipid Metabolism Abnormalities in Obesity and Clear Cell Renal Cell Carcinoma

Bobulescu, I. Alexandru; Pop, Laurentiu M.; Mani, Chinnadurai; Turner, Kala; Rivera, Cristian; Khatoon, Sabiha; Kairamkonda, Subash; Hannan, Raquibul; Palle, Komaraiah

doi:10.3390/metabo11090608

Cited by 22 publications

(16 citation statements)

References 139 publications

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“…A lower expression of CPT1 is associated with poor patient outcomes [36]. Altering lipid metabolism may be a new therapeutic avenue for ccRCC [37][38][39]. In line with these studies, the miR-21silencing strategy is of potential interest in ccRCC treatment since PTEN, a potent inhibitor of the PI3K/AKT pathway, and PPAR-α are direct targets of miR-21.…”

Section: Discussionmentioning

confidence: 93%

A Double-Negative Feedback Interaction between miR-21 and PPAR-α in Clear Renal Cell Carcinoma

Goujon

Woszczyk

Gaudelot

et al. 2022

Cancers

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Clear cell renal cell carcinoma (ccRCC) is the main histotype of kidney cancer, which is typically highly resistant to conventional therapies and known for abnormal lipid accumulation. In this context, we focused our attention on miR-21, an oncogenic miRNA overexpressed in ccRCC, and peroxysome proliferator-activated receptor-α (PPAR- α), one master regulator of lipid metabolism targeted by miR-21. First, in a cohort of 52 primary ccRCC samples, using RT-qPCR and immunohistochemistry, we showed that miR-21 overexpression was correlated with PPAR-α downregulation. Then, in ACHN and 786-O cells, using RT-qPCR, the luciferase reporter gene, chromatin immunoprecipitation, and Western blotting, we showed that PPAR-α overexpression (i) decreased miR-21 expression, AP-1 and NF-κB transcriptional activity, and the binding of AP-1 and NF-κB to the miR-21 promoter and (ii) increased PTEN and PDCD4 expressions. In contrast, using pre-miR-21 transfection, miR-21 overexpression decreased PPAR-α expression and transcriptional activity mediated by PPAR-α, whereas the anti-miR-21 (LNA-21) strategy increased PPAR-α expression, but also the expression of its targets involved in fatty acid oxidation. In this study, we showed a double-negative feedback interaction between miR-21 and PPAR-α. In ccRCC, miR-21 silencing could be therapeutically exploited to restore PPAR-α expression and consequently inhibit the oncogenic events mediated by the aberrant lipid metabolism of ccRCC.

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Section: Discussionmentioning

confidence: 93%

A Double-Negative Feedback Interaction between miR-21 and PPAR-α in Clear Renal Cell Carcinoma

Goujon

Woszczyk

Gaudelot

et al. 2022

Cancers

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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 [34,35,61]. Reducing the lipid content of our diets may, therefore, be important to increase their anticancer activity.…”

Section: Discussionmentioning

confidence: 99%

Manipulation of Amino Acid Levels with Artificial Diets Induces a Marked Anticancer Activity in Mice with Renal Cell Carcinoma

Calderón-Montaño

Guillén-Mancina

Jiménez-Alonso

et al. 2022

IJMS

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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 screened 18 artificial diets for anticancer activity in a challenging animal model of renal cell carcinoma. The model was established 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 and mechanism of action of this simple and inexpensive anticancer strategy.

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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%

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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Renal Lipid Metabolism Abnormalities in Obesity and Clear Cell Renal Cell Carcinoma

Cited by 22 publications

References 139 publications

A Double-Negative Feedback Interaction between miR-21 and PPAR-α in Clear Renal Cell Carcinoma

A Double-Negative Feedback Interaction between miR-21 and PPAR-α in Clear Renal Cell Carcinoma

Manipulation of Amino Acid Levels with Artificial Diets Induces a Marked Anticancer Activity in Mice with Renal Cell Carcinoma

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

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