GSK-3 inhibitor inhibits cell proliferation and induces apoptosis in human osteosarcoma cells

Abstract

Glycogen synthase kinase-3 (GSK-3) is a serine/threonine kinase that functions in numerous signaling pathways initiated by diverse stimuli. The functions of GSK-3 in cancer differ depending on cell type. In the present study, we examined the effects of a specific GSK-3 inhibitor on the regulation of osteosarcoma cell proliferation and apoptosis. Immunohistochemical analysis and real-time reverse transcription-polymerase chain reaction (RT-PCR) were performed to determine the expression pattern of GSK-3 in human osteosarcoma cells. We used the MTS assay, western blotting, measurement of single-stranded DNA and morphological analyses to study the effects of a GSK-3 inhibitor, SB216763 on osteosarcoma cell proliferation and survival. We detected an increase in mRNA expression of GSK-3 and aberrant nuclear accumulation of GSK-3 in the osteosarcoma cells. Pharmacological inhibition of GSK-3 led to a decrease in proliferation and survival of osteosarcoma cells. Inhibition of GSK-3 resulted in a decreased expression of Bcl-2 and a subsequent increase in osteosarcoma cell apoptosis via the mitochondrial pathway. The present study demonstrated that GSK-3 activity is critical for tumorigenicity and cell survival in osteosarcoma cells. Our findings suggest that GSK-3 is a potential therapeutic target for the treatment of human osteosarcoma.

Glycogen Synthase Kinase 3β in Cancer Biology and Treatment

“…The most pronounced and common hallmark property of cancer is persistent tumor cell survival with evasion of apoptosis and proliferation [179]. As shown in Table 1, GSK3β sustains tumor cell survival in many cancer types by exploiting various pro-survival pathways mediated by nuclear factor (NF)κ-B [48,[52][53][54][55]63,78,94,95,98,107,128,129,151,153], Hh/Gli [43], mammalian target of rapamycin (mTOR) [97,140] and signal transducers and activators of transcription (STAT)3 [27,68]. Additionally, GSK3β helps tolerate apoptotic stimuli induced by the tumor necrosis factor-related apoptosis inducing ligand (TRAIL) receptor-dependent synthetic lethal system [36,57,61,71,74,83,107].…”

“…Recently, our group and others reported a therapeutic effect of GSK3β inhibition against osteosarcoma [151][152][153][154], rhabdomyosarcoma [155,156], synovial sarcoma and fibrosarcoma [157]. These malignancies comprise the majority of sarcomas encountered in orthopedics for surgical removal.…”

Glycogen synthase kinase 3β in tumorigenesis and oncotherapy (Review)

“…Notably, GSK 3β inhibitor, SB216763, comparatively decreases the proliferation of GBM cells and induces apoptosis of GBM cells by halting DSB repair. Similarly, it has been revealed that GSK 3β inhibitor could block the NF-κB pathway and reduce the NF-κB-mediated transcription in osteosarcoma (OSA) ( 76 ).…”

Molecular Pathways: Revisiting Glycogen Synthase Kinase-3β as a Target for the Treatment of Cancer

“…Using a number of toolkit inhibitors of GSK-3β, translational studies credentialed GSK-3β as a therapeutic target in multiple tumor types including pancreatic cancer (8, 9), chronic lymphocytic leukemia (10), colon (11), renal (12) and bladder (13) cancer. More recent studies have also shown that the inhibition of GSK-3β suppressed cancer cell viability in models of glioblastoma (14–16), leukemia (17–20), neuroblastoma (21, 22), osteosarcoma (23), melanoma (24), ovarian (25, 26), thyroid (27), prostate (28–30), breast (31–33) and lung cancer (34, 35). Thus, GSK-3β has emerged as a viable therapeutic target for the treatment of a broad spectrum of different cancer types.…”