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ABL1, a new target of oxidative stress related rental cancer

 

Altered metabolic programs and consequent changes of stress response pathways are emerging causes of lots cancers. Sourbier et al. used hereditary kidney cancers as a model to investigate mechanism-based therapeutic interventions by metabolic adaptations. They found the activation of Abelson murine leukemia viral oncogene homolog 1 (ABL1), an proto-oncogene, is critical in tumors that relate to glycolysis and oxidative stress. The article was published on Cancer Cell, recently.

 

The mutation of fumarate hydratase (FH) causes accumulation of fumarate, disruption of mitochondrial respiration and dependence on aerobic glycolysis, lead to aggressive renal cell carcinoma (HLRCC). Excess fumarate promotes ABL1 activity indirectly, consequently leads to the increase of aerobic glycolysis and neutralization of proteotoxic stress via mTOR/HIF1α and transcription factor nuclear factor-like 2 (NRF2), respectively. In addition, NRF2 is an critical factor of HLRCC tumor development and progressing. The results were verified by the restoration of FH, which caused decrease of ABL1 activity and the cytotoxicity induced by the inhibition of ABL1. In conclusion, the findings indicates ABL1 is a key factor modulates fumarate-dependent cellular stress response, and may contribute to clinical strategy against oxidatively stressed tumors with high glycolysis level.

 

Reference:
Cancer Cell. 2014 Dec 8;26(6):840-50.

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