Gatekeeper to cancer senescence
21.05.2013 - Dutch cancer experts have found an enzyme that seems to induce cancer senescence.
When oncogenes are activated inside a cell, they normally mobilise tumour suppressor networks which can act like a brake to cancer through a process termed oncogene-induced senescence (OIS). They withdraw proliferating cells almost irreversibly, providing protection against malignant transformation. Now, a research team led by Daniel Peeper from the Netherland’s Cancer Institute in Amsterdam has identified a metabolic gate-keeper of the process.
Using metabolic and functional analyses of melanoma cells carrying the common BRAFV600E mutation, the team of Dutch, Scottish, Belgian, Spanish, Israeli and US researchers identified the TCA enzyme pyruvate dehydrogenase (PDH) as a crucial mediator of cancer senescence. BRAFV600E-induced senescence was accompanied by simultaneous suppression of the PDH-inhibitory enzyme pyruvate dehydrogenase kinase 1 (PDK1) and induction of the PDH-activating enzyme pyruvate dehydrogenase phosphatase 2 (PDP2). The resulting combined activation of PDH enhanced the use of pyruvate in the tricarboxylic acid cycle, causing increased respiration and redox stress.
Enforced normalisation of either PDK1 or PDP2 expression levels inhibited PDH and abrogated oncogene-induced senescence. Depletion of PDK1 eradicated melanoma subpopulations resistant to targeted BRAF inhibition, and caused regression of established melanomas. The results suggest a mechanistically new therapeutic route to induce cancer senescence and stop tumour cell proliferation at its earliest stages.