Abstract
Resistance to genotoxic therapies is a primary cause of treatment failure and tumor recurrence. The underlying mechanisms that activate the DNA damage response (DDR) and allow cancer cells to escape the lethal effects of genotoxic therapies remain unclear. Here, we uncover an unexpected mechanism through which pyruvate kinase M2 (PKM2), the highly expressed PK isoform in cancer cells and a master regulator of cancer metabolic reprogramming, integrates with the DDR to directly promote DNA double-strand break (DSB) repair. In response to ionizing radiation and oxidative stress, ATM phosphorylates PKM2 at T328 resulting in its nuclear accumulation. pT328-PKM2 is required and sufficient to promote homologous recombination (HR)-mediated DNA DSB repair through phosphorylation of CtBP-interacting protein (CtIP) on T126 to increase CtIP’s recruitment at DSBs and resection of DNA ends. Disruption of the ATM-PKM2-CtIP axis sensitizes cancer cells to a variety of DNA-damaging agents and PARP1 inhibition. Furthermore, increased nuclear pT328-PKM2 level is associated with significantly worse survival in glioblastoma patients. Combined, these data advocate the use of PKM2-targeting strategies as a means to not only disrupt cancer metabolism but also inhibit an important mechanism of resistance to genotoxic therapies.
Highlights
Resistance to genotoxic therapies, such as radiation and DNAdamaging chemotherapeutics, is the primary cause of treatment failure for many cancers
Identification of ataxia telangiectasia mutated (ATM) substrates and/or CtBP-interacting protein (CtIP) effectors that are vital to DNA double-strand break (DSB) repair in cancer cells but are dispensable to repair in normal cells could provide essential tools to combat treatment resistance
pyruvate kinase M2 (PKM2) is a critical mediator of cellular resistance to DNA-damaging treatment To investigate the role of PKM2 in cancer cell resistance to DNAdamaging therapies, we stably knocked down PKM2 in the human glioblastoma multiforme (GBM) U87 cell line, which expresses high endogenous levels of PKM29 (Supplementary information, Fig. S1a), and subjected these cells to ionizing radiation (IR)
Summary
Resistance to genotoxic therapies, such as radiation and DNAdamaging chemotherapeutics, is the primary cause of treatment failure for many cancers. The serine/threonine kinase ataxia telangiectasia mutated (ATM) is a key protein kinase that regulates multiple DDR processes including DNA repair through the NHEJ and HR pathways.[3] While both the NHEJ and HR pathways are involved in cancer resistance to genotoxic therapies, the HR repair pathway is critical in highly proliferative cancer cells. CtBP-interacting protein (CtIP) is a key ratelimiting component of HR repair that interacts with the Mre11/ Rad50/Nbs[1] (MRN) complex to promote DSB end-resection, generation of ssDNA tails, and initiation of DSB repair.[4] While ATM and CtIP are indisputably important mediators of cancer resistance to genotoxic agents, efforts to reduce cancer cell resistance to therapy via directly targeting these molecules are inherently limited given their essential functions in normal cells. Identification of ATM substrates and/or CtIP effectors that are vital to DNA DSB repair in cancer cells but are dispensable to repair in normal cells could provide essential tools to combat treatment resistance
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