Novel targets in altered tumour metabolism in kidney cancer

Minton, Denise R.; Nanus, David M.

doi:10.1038/nrurol.2015.168

Cited by 6 publications

(4 citation statements)

References 11 publications

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“…Studies showed that the initiation and execution of ferroptosis are tightly linked to the metabolism of amino acid, iron, and polyunsaturated fatty acid [25]. As it happens, metabolic reprogramming is the prominent feature of RCC, such that this cancer is labeled a metabolic disease [26]. Therefore, it is legitimate to assume that RCC possesses superior sensitivity to ferroptosis.…”

Section: Discussionmentioning

confidence: 99%

PDIA4 confers resistance to ferroptosis via induction of ATF4/SLC7A11 in renal cell carcinoma

et al. 2023

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The prognosis of renal cell carcinoma (RCC) remains poor due to metastases and resistance to chemotherapy. Salinomycin (Sal) exhibits the potential of antitumor, while the underlying mechanism is not completely clear. Here, we found that Sal induced ferroptosis in RCCs and identified Protein Disulfide Isomerase Family A Member 4 (PDIA4) as a mediator of Sal’s effect on ferroptosis. Sal suppressed PDIA4 by increasing its autophagic degradation. Downregulation of PDIA4 increased the sensitivity to ferroptosis, while ectopic overexpression of PDIA4 conferred ferroptosis resistance to RCCs. Our data showed that downregulation of PDIA4 suppressed activating transcription factor 4 (ATF4) and its downstream protein SLC7A11 (solute carrier family 7 member 11), thereby aggravating ferroptosis. In vivo, the administration of Sal promoted ferroptosis and suppressed tumor progress in the xenograft mouse model of RCC. Bioinformatical analyses based on clinical tumor samples and database indicated a positive correlation exists between PDIA4 and PERK/ATF4/SLC7A11 signaling pathway, as well as the malignant prognosis of RCCs. Together, our findings reveal that PDIA4 promotes ferroptosis resistance in RCCs. Treatment of Sal sensitizes RCC to ferroptosis via suppressing PDIA4, suggesting the potential therapeutical application in RCCs.

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Section: Discussionmentioning

confidence: 99%

PDIA4 confers resistance to ferroptosis via induction of ATF4/SLC7A11 in renal cell carcinoma

et al. 2023

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“…One of the most profound increases is that of Ndufa4l2, a mitochondrial protein shown to be required for proliferation and colony formation in kidney cancer cell lines ( 10 , 15 ). Importantly, Ndufa4l2 is also elevated in human ccRCC ( 15 , 38 ), and this high expression in cancer makes NDUFA4L2 a promising target for therapeutic approaches. In the present study, we decreased Ndufa4l2 expression in our TRACK ccRCC animal model to evaluate the effects of targeting Ndufa4l2.…”

Section: Discussionmentioning

confidence: 99%

“…cancer cell lines (10,15). Importantly, Ndufa4l2 is also elevated in human ccRCC (15,38), and this high expression in cancer makes NDUFA4L2 a promising target for therapeutic approaches. In the present study, we decreased Ndufa4l2 expression in our TRACK ccRCC animal model to evaluate the effects of targeting Ndufa4l2.…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial Ndufa4l2 Enhances Deposition of Lipids and Expression of Ca9 in the TRACK Model of Early Clear Cell Renal Cell Carcinoma

et al. 2021

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Mitochondrial dysfunction and aberrant glycolysis are hallmarks of human clear cell renal cell carcinoma (ccRCC). Whereas glycolysis is thoroughly studied, little is known about the mitochondrial contribution to the pathology of ccRCC. Mitochondrial Ndufa4l2 is predictive of poor survival of ccRCC patients, and in kidney cancer cell lines the protein supports proliferation and colony formation. Its role in ccRCC, however, remains enigmatic. We utilized our established ccRCC model, termed Transgenic Cancer of the Kidney (TRACK), to generate a novel genetically engineered mouse model in which dox-regulated expression of an shRNA decreases Ndufa4l2 levels specifically in the renal proximal tubules (PT). This targeted knockdown of Ndufa4l2 reduced the accumulation of neutral renal lipid and was associated with decreased levels of the ccRCC markers carbonic anhydrase 9 (CA9) and Enolase 1 (ENO1). These findings suggest a link between mitochondrial dysregulation (i.e. high levels of Ndufa4l2), lipid accumulation, and the expression of ccRCC markers ENO1 and CA9, and demonstrate that lipid accumulation and ccRCC development can potentially be attenuated by inhibiting Ndufa4l2.

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“…For example, the Warburg effect (aerobic glycolysis), arginine synthetic abnormalities (caused by arginosuccinate synthetase-1 deficiency), and glutamine pathway reprogramming are all pronounced in RCC. The recent elucidation of the metabolic abnormalities that occur in RCC 10,11 (Figure 1) is not only useful for understanding how this tumor can be so difficult to treat, but also, these data turn out to be a gold mine for therapeutic exploration. Indeed, targeted therapy using pathwayspecific inhibitors (which in some cases, are compounds that were discarded after their discovery) would show high specificity with fewer adverse effects; such an approach will be discussed below.…”

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confidence: 99%

The Nephrologist’s Tumor: Basic Biology and Management of Renal Cell Carcinoma

Chang

Perazella

et al. 2016

JASN

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Kidney cancer, or renal cell carcinoma (RCC), is a disease of increasing incidence that is commonly seen in the general practice of nephrology. However, RCC is underrecognized by the nephrology community, such that its presence in curricula and research by this group is lacking. In the most common form of RCC, clear cell renal cell carcinoma (ccRCC), inactivation of the von Hippel-Lindau tumor suppressor is nearly universal; thus, the biology of ccRCC is characterized by activation of hypoxia-relevant pathways that lead to the associated paraneoplastic syndromes. Therefore, RCC is labeled the internist's tumor. In light of this characterization and multiple other metabolic abnormalities recently associated with ccRCC, it can now be viewed as a metabolic disease. In this review, we discuss the basic biology, pathology, and approaches for treatment of RCC. It is important to distinguish between kidney confinement and distant spread of RCC, because this difference affects diagnostic and therapeutic approaches and patient survival, and it is important to recognize the key interplay between RCC, RCC therapy, and CKD. Better understanding of all aspects of this disease will lead to optimal patient care and more recognition of an increasingly prevalent nephrologic disease, which we now appropriately label the nephrologist's tumor.

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Novel targets in altered tumour metabolism in kidney cancer

Abstract: Refers to Wettersten, H. I. et al. Grade-dependent metabolic reprogramming in kidney cancer revealed by combined proteomics and metabolomics analysis. Cancer Res. http://dx.

Cited by 6 publications

References 11 publications

PDIA4 confers resistance to ferroptosis via induction of ATF4/SLC7A11 in renal cell carcinoma

PDIA4 confers resistance to ferroptosis via induction of ATF4/SLC7A11 in renal cell carcinoma

Mitochondrial Ndufa4l2 Enhances Deposition of Lipids and Expression of Ca9 in the TRACK Model of Early Clear Cell Renal Cell Carcinoma

The Nephrologist’s Tumor: Basic Biology and Management of Renal Cell Carcinoma

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