Abstract
Glycogen Synthase Kinase-3 alpha (GSK3A) and beta (GSK3B) isoforms are encoded by distinct genes, are 98% identical within their kinase domain and perform similar functions in several settings; however, they are not completely redundant and, depending on the cell type and differentiative status, they also play unique roles. We recently identified a role for GSK3B in drug resistance by demonstrating that its inhibition enables necroptosis in response to chemotherapy in p53-null drug-resistant colon carcinoma cells. We report here that, similarly to GSK3B, also GSK3A silencing/inhibition does not affect cell proliferation or cell cycle but only abolishes growth after treatment with DNA-damaging chemotherapy. In particular, blocking GSK3A impairs DNA repair upon exposure to DNA-damaging drugs. As a consequence, p53-null cells overcome their inability to undergo apoptosis and mount a necroptotic response, characterized by absence of caspase activation and RIP1-independent, PARP-dependent AIF nuclear re-localization. We therefore conclude that GSK3A is redundant with GSK3B in regulating drug-resistance and chemotherapy-induced necroptosis and suggest that inhibition of only one isoform, or rather partial inhibition of overall cellular GSK3 activity, is enough to re-sensitize drug-resistant cells to chemotherapy.
Highlights
Two different GSK3 isoforms, Glycogen Synthase Kinase-3 alpha (GSK3A) and GSK3B, encoded by distinct genes, but 98% identical within their kinase domain, are expressed in mammalian cells [1]
We observed that, in absence of GSK3A expression, HCT116p53KO cells were resensitized to druginduced cytotoxicity and showed a cell death response similar to that of parental drug-sensitive HCT116 cells (Fig. 2B); same results were obtained in absence of GSK3B expression
GSK3A, but not GSK3B, has been identified as a therapeutic target in melanoma [15] suggesting that, to what has been reported for normal cells, the two isoforms can play both distinct or redundant roles depending on the cancer cell type
Summary
Two different GSK3 isoforms, GSK3A and GSK3B, encoded by distinct genes, but 98% identical within their kinase domain, are expressed in mammalian cells [1] Both isoforms perform similar functions in several settings, but they are not completely redundant as demonstrated by gene knockout studies. Functional redundancy instead has been demonstrated in the control of several regulatory proteins, in the production of beta-amyloid peptides associated with Alzheimer’s disease and in cell cycle and proliferation. In the latter, both isoforms play an anti-proliferative role by promoting APC-dependent phosphorylation of b-catenin a transcription factor positively regulating Myc and cyclin D1 expression – targeting it to proteasome-mediated degradation [7]. Very little is known about GSK3A role in cancer cells
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