title: RSK promotes G2 DNA damage checkpoint silencing and participates in melanoma chemoresistance.
abstract: The incidence of malignant melanoma is growing rapidly worldwide and there is still no effective therapy for metastatic disease. This type of cancer is highly resistant to conventional DNA-damaging chemotherapeutics, and intense research has been dedicated for understanding the molecular pathways underlying chemoresistance. The Ras/mitogen-activated protein kinase (MAPK) signalling pathway is often deregulated in melanoma, which frequently harbours activating mutations in NRAS or BRAF. Herein, we demonstrate that the MAPK-activated protein kinase RSK (p90 ribosomal S6 kinase) contributes to melanoma chemoresistance by altering their response to chemotherapeutic agents. We find that RSK phosphorylates checkpoint kinase 1 (Chk1) at an inhibitory site, Ser280, both in vitro and in vivo. Our results indicate that RSK is the predominant protein kinase operating downstream of mitogens and oncogenes of the Ras/MAPK pathway, and consistent with this, we find that RSK constitutively phosphorylates Chk1 in melanoma. We show that RSK inhibition increases Chk1 activity in response to DNA-damaging agents, suggesting that the Ras/MAPK pathway modulates Chk1 function and the response to DNA damage. Accordingly, we demonstrate that RSK promotes G2 DNA damage checkpoint silencing in a Chk1-dependent manner, and find that RSK inhibitors sensitize melanoma cells to DNA-damaging agents. 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.
authors.affiliation: Institute for Research in Immunology and Cancer (IRIC), Université de Montréal, Montreal, Quebec, Canada.
authors.forename: H
authors.initials: H
authors.lastname: Ray-David
authors.forename: Y
authors.initials: Y
authors.lastname: Romeo
authors.forename: G
authors.initials: G
authors.lastname: Lavoie
authors.forename: P
authors.initials: P
authors.lastname: Déléris
authors.forename: J
authors.initials: J
authors.lastname: Tcherkezian
authors.forename: J A
authors.initials: JA
authors.lastname: Galan
authors.forename: P P
authors.initials: PP
authors.lastname: Roux
mesh_terms: D002460:Cell Line; D000071877:Checkpoint Kinase 1; D004249:DNA Damage; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D059565:G2 Phase Cell Cycle Checkpoints; D020868:Gene Silencing; D006801:Humans; D008545:Melanoma / Q000235:genetics* / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011494:Protein Kinases / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D047428:Protein Kinase Inhibitors; D011494:Protein Kinases; D019869:Phosphatidylinositol 3-Kinases; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; D038744:Ribosomal Protein S6 Kinases, 90-kDa; D020928:Mitogen-Activated Protein Kinases; D016283:Proto-Oncogene Proteins p21(ras)