Promotes G2 DNA damage checkpoint silencing; inhibitors sensitize melanoma cells to DNA damage
MONDAY, Nov. 5 (HealthDay News) -- The mitogen-activated protein kinase (MAPK) p90 ribosomal S6 kinase (RSK) appears to play a role in the poor response of melanoma cells to DNA-damaging agents, according to research published online Oct. 29 in Oncogene.
Hind Ray-David, Ph.D., from the Université de Montréal, and colleagues studied the Ras/MAPK-signaling pathway, which is often deregulated in melanoma.
The researchers found that MAPK-activated protein kinase RSK played a role in melanoma chemoresistance by altering the response to chemotherapeutic agents. In in-vivo and in-vitro experiments, RSK phosphorylated checkpoint kinase 1 (Chk1) at Ser280, an inhibitory site. RSK was found to be the main protein kinase operating downstream of mitogens and oncogenes of the Ras/MAPK pathway, and, in melanoma, RSK constitutively phosphorylated Chk1. In response to DNA-damaging agents, RSK inhibition increased Chk1 activity. RSK promoted silencing of the G2 DNA damage checkpoint in a Chk1-dependent manner. Furthermore, RSK inhibitors were found to sensitize melanoma cells to agents which induce DNA damage.
"Together, our results identify a novel link between the Ras/MAPK pathway and the DNA damage response, and suggest that RSK inhibitors may be used to modulate chemosensitivity, which is one of the major obstacles to melanoma treatment," Ray-David and colleagues conclude.
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