A cancer ubiquitome landscape identifies metabolic reprogramming as target of Parkin tumor suppression

Area of Science:

• Oncology
• Metabolic pathways
• Mitochondrial dynamics

Background:

• Metabolic reprogramming, including mitochondrial and glycolytic networks, is a hallmark of cancer.
• The precise role of these metabolic changes in cancer progression remains incompletely understood.

Purpose of the Study:

• To investigate the function of Parkin, an E3 ubiquitin ligase, in cancer metabolism and tumor suppression.
• To elucidate the mechanisms by which Parkin affects cellular metabolism and tumor growth.

Main Methods:

• Global proteomics and ubiquitome screening.
• Analysis of Parkin's impact on mitochondrial dynamics and the pentose phosphate pathway.
• Assessment of tumor cell movement, oxidative stress, and tumor growth in vivo.

Main Results:

• Parkin inhibits mitochondrial dynamics and the non-oxidative pentose phosphate pathway.
• Parkin suppresses tumor cell movement, induces metabolic and oxidative stress, and inhibits primary and metastatic tumor growth.
• Parkin's tumor suppressive function requires its E3 ligase activity, is reversed by antioxidants, and is independent of mitophagy.

Conclusions:

• Parkin acts as an endogenous tumor suppressor by targeting cancer metabolic networks.
• Disruption of mitochondrial dynamics and the pentose phosphate pathway by Parkin are key mechanisms of tumor suppression.
• Cancer metabolic networks can be potent oncogenes targeted by endogenous tumor suppressors like Parkin.