Glycogen Synthase Kinase 3 Protein Kinase Activity Is Frequently Elevated in Human Non-Small Cell Lung Carcinoma and Supports Tumour Cell Proliferation

Abstract

BackgroundGlycogen synthase kinase 3 (GSK3) is a central regulator of cellular metabolism, development and growth. GSK3 activity was thought to oppose tumourigenesis, yet recent studies indicate that it may support tumour growth in some cancer types including in non-small cell lung carcinoma (NSCLC). We examined the undefined role of GSK3 protein kinase activity in tissue from human NSCLC.MethodsThe expression and protein kinase activity of GSK3 was determined in 29 fresh frozen samples of human NSCLC and patient-matched normal lung tissue by quantitative immunoassay and western blotting for the phosphorylation of three distinct GSK3 substrates in situ (glycogen synthase, RelA and CRMP-2). The proliferation and sensitivity to the small-molecule GSK3 inhibitor; CHIR99021, of NSCLC cell lines (Hcc193, H1975, PC9 and A549) and non-neoplastic type II pneumocytes was further assessed in adherent culture.ResultsExpression and protein kinase activity of GSK3 was elevated in 41% of human NSCLC samples when compared to patient-matched control tissue. Phosphorylation of GSK3α/β at the inhibitory S21/9 residue was a poor biomarker for activity in tumour samples. The GSK3 inhibitor, CHIR99021 dose-dependently reduced the proliferation of three NSCLC cell lines yet was ineffective against type II pneumocytes.ConclusionNSCLC tumours with elevated GSK3 protein kinase activity may have evolved dependence on the kinase for sustained growth. Our results provide further important rationale for exploring the use of GSK3 inhibitors in treating NSCLC.

Glycogen synthase kinase‐3β is a pivotal mediator of cancer invasion and resistance to therapy

“…This effect has been observed not only in gastrointestinal and pancreatic cancer cells but also in glioblastoma, osteosarcoma (S. Shimozaki, N. Yamamoto, T. Domoto, H. Nishida, K. Hayashi, H. Kimura, A. Takeuchi, S. Miwa, K. Igarashi, T. Kato, Y. Aoki, T. Higuchi, M. Hirose, R.M. Hoffman, T. Minamoto, H. Tsuchiya, unpublished data, 2016) and other malignant neoplasms such as gynecological and urogenital cancers, soft tissue sarcomas, hematological malignancies and lung cancers . This accumulating evidence firmly establishes GSK3β as a valuable target in cancer treatment …”

“…This effect has been observed not only in gastrointestinal and pancreatic cancer cells (28)(29)(30)(32)(33)(34)(35) but also in glioblastoma, (31,36,37) (38) and other malignant neoplasms such as gynecological and urogenital cancers, (39)(40)(41)(42)(43)(44)(45)(46)(47) soft tissue sarcomas, (48,49) hematological malignancies (50,51) and lung cancers. (52,53) This accumulating evidence firmly establishes GSK3b as a valuable target in cancer treatment. (11,12) There has been substantial interest in the molecular mechanisms by which GSK3b favors tumor progression and by which inhibition of its activity or expression attenuates tumor cell survival, immortalization and proliferation.…”

DRP5 is involved in cancer cell growth and predicts poor prognosis in human osteosarcoma

“…CRMP-1 is suggested to be a cancer suppressor [17,31,32], while LCRMP-1 functions to promote cancer metastasis [19,33,34]. CRMP-2 was suggested as a prognostic marker and candidate therapeutic target in NSCLC and colorectal carcinoma [20,[35][36][37]. Regarding DRP5, its neuronal autoantibody was reported to be related with patients at risk for lung carcinoma [22,38,39].…”

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.…”