Glycogen synthase kinase 3β as a potential therapeutic target in synovial sarcoma and fibrosarcoma

Abstract

derived growth factor; pGSK3β S9 , GSK3β phosphorylated in S9 residue; pGSK3β Y216 , GSK3β phosphorylated in Y216 residue; RTK(s), receptor-type tyrosine kinase(s) AbstractSoft tissue sarcomas (STSs) are a rare cancer type. Almost half are unresponsive to multi-pronged treatment and might therefore benefit from biologically targeted therapy. An emerging target is glycogen synthase kinase (GSK)3β, which is implicated in various diseases including cancer. Here, we investigated the expression, activity and putative pathological role of GSK3β in synovial sarcoma and fibrosarcoma, comprising the majority of STS that are encountered in orthopedics. Expression of the active form of GSK3β (tyrosine 216-phosphorylated) was higher in synovial sarcoma (SYO-1, HS-SY-II, SW982) and in fibrosarcoma (HT1080) tumor cell lines than in untransformed fibroblast (NHDF) cells that are assumed to be the normal mesenchymal counterpart cells. Inhibition of GSK3β activity by pharmacological agents (AR-A014418, SB-216763) or of its expression by RNA interference suppressed the proliferation of sarcoma cells and their invasion of collagen gel, as well as inducing their apoptosis.These effects were associated with G0/G1-phase cell cycle arrest and decreased expression of cyclin D1, cyclin-dependent kinase (CDK)4 and matrix metalloproteinase 2. Intraperitoneal injection of the GSK3β inhibitors attenuated the growth of SYO-1 and HT1080 xenografts in athymic mice without obvious detrimental effects. It also mitigated cell proliferation and induced apoptosis in the tumors of mice. This study indicates that increased activity of GSK3β in synovial sarcoma and fibrosarcoma sustains tumor proliferation and invasion through the cyclin D1/CDK4-mediated pathway and enhanced extracellular matrix degradation. Our results provide a biological basis for GSK3β as a new and promising therapeutic target for these STS types. K E Y W O R D Scell cycle, glycogen synthase kinase 3β, invasion, migration, soft tissue sarcoma

Glycogen Synthase Kinase 3β in Cancer Biology and Treatment

“…These functions depend on its subcellular localization in the cell membrane and nucleus and are responsible for tumor-suppressive and tumor-promoting roles, respectively, in several cancer types including colorectal cancer [180,181]. Paradoxically, the induction of Wnt/β-catenin signaling through inhibition of GSK3β has been shown to suppress tumor cell survival and proliferation in osteosarcoma and rhabdomyosarcoma [152,157], pancreatic cancer and non-small cell lung cancer (NSCLC) [51,70,77]. This indirectly supports the notion that β-catenin acts as a tumor suppressor in these tumors (reviewed in [15]).…”

“…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.…”

“…Sustained activity of human telomerase reverse transcriptase (hTERT) and telomerase in response to aberrant GSK3β contributes to the immortalization of tumor cells from the colon and rectum, pancreas, liver, lung, urinary bladder, ovary and uterine cervix [ 29 , 38 ]. Cell proliferation pathways mediated by c-Myc, cyclin D1 and STAT3 can promote unrestrained GSK3β-dependent tumor cell proliferation [ 51 , 52 , 53 , 68 , 97 , 101 , 102 , 107 , 109 , 113 , 122 , 126 , 157 ].…”

The Role of GSK-3 in Cancer Immunotherapy: GSK-3 Inhibitors as a New Frontier in Cancer Treatment

“…AR-A014418, an ATP-competitive and selective GSK-3β inhibitor, has been reported to suppress the proliferation and induce the apoptosis of gastric cancer [36], synovial sarcoma, and fibrosarcoma cells in vitro as well as in vivo [37].…”

Table_3.XLSX

“…Zhang et al, 2019), and inhibition of it was considered efficient in suppressing tumor growth (Edderkaoui et al, 2018;Wu et al, 2019). Moreover, there have been many studies on GSK3B inhibitors, including Metavert molecule in PAAD (Edderkaoui et al, 2018), BT-000775 molecule in BRCA (Ogunleye et al, 2019), BIO molecule in TNBCs (triple-negative breast cancers) (Vijay et al, 2019), AR-A014418 and SB-216763 molecules in STSs (soft tissue sarcomas) (Abe et al, 2020), etc.…”