AKT1 Is Required for a Complete Palbociclib-Induced Senescence Phenotype in BRAF-V600E-Driven Human Melanoma

Cellular senescence is a carefully regulated process of proliferative arrest accompanied by functional and morphologic changes. Senescence allows damaged cells to avoid neoplastic proliferation; however, the induction of the senescence-associated secretory phenotype (SASP) can promote tumor growth....

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Bibliographic Details
Published in:Cancers 2022-01, Vol.14 (3), p.572
Main Authors: Bayer, Abraham L, Pietruska, Jodie, Farrell, Jaymes, McRee, Siobhan, Alcaide, Pilar, Hinds, Philip W
Format: Article
Language:English
Subjects:
AKT protein
AKT1 protein
Cancer
Cancer therapies
Cell cycle
Cell proliferation
Clinical trials
CRISPR
Cyclin-dependent kinase 4
Genotype & phenotype
Isoforms
Kinases
Medical prognosis
Melanoma
NF-κB protein
Phenotypes
Phosphorylation
Proteins
Senescence
Tumor cells
Tumors
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Summary:Cellular senescence is a carefully regulated process of proliferative arrest accompanied by functional and morphologic changes. Senescence allows damaged cells to avoid neoplastic proliferation; however, the induction of the senescence-associated secretory phenotype (SASP) can promote tumor growth. The complexity of senescence may limit the efficacy of anti-neoplastic agents, such as CDK4/6 inhibitors (Cdk4/6i), that induce a senescence-like state in tumor cells. The AKT kinase family, which contains three isoforms that play both unique and redundant roles in cancer progression, is commonly hyperactive in many cancers including melanoma and has been implicated in the regulation of senescence. To interrogate the role of AKT isoforms in Cdk4/6i-induced cellular senescence, we generated isoform-specific AKT knockout human melanoma cell lines. We found that the CDK4/6i Palbociclib induced a form of senescence in these cells that was dependent on AKT1. We then evaluated the activity of the cGAS-STING pathway, recently implicated in cellular senescence, finding that cGAS-STING function was dependent on AKT1, and pharmacologic inhibition of cGAS had little effect on senescence. However, we found SASP factors to require NF-κB function, in part dependent on a stimulatory phosphorylation of IKKα by AKT1. In summary, we provide the first evidence of a novel, isoform-specific role for AKT1 in therapy-induced senescence in human melanoma cells acting through NF-κB but independent of cGAS.
ISSN:2072-6694
2072-6694
DOI:10.3390/cancers14030572