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Glycogen synthase kinase-3 beta inhibitors as novel cancer treatments and modulators of antitumor immune responses.

ABSTRACT: As a kinase at the crossroads of numerous metabolic and cell growth signaling pathways, glycogen synthase kinase-3 beta (GSK-3?) is a highly desirable therapeutic target in cancer. Despite its involvement in pathways associated with the pathogenesis of several malignancies, no selective GSK-3? inhibitor has been approved for the treatment of cancer. The regulatory role of GSK-3? in apoptosis, cell cycle, DNA repair, tumor growth, invasion, and metastasis reflects the therapeutic relevance of this target and provides the rationale for drug combinations. Emerging data on GSK-3? as a mediator of anticancer immune response also highlight the potential clinical applications of novel selective GSK-3? inhibitors that are entering clinical studies. This manuscript reviews the preclinical and early clinical results with GSK-3? inhibitors and delineates the developmental therapeutics landscape for this potentially important target in cancer therapy.

SUBMITTER: Sahin I

PROVIDER: S-EPMC6606036 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Glycogen synthase kinase-3 beta inhibitors as novel cancer treatments and modulators of antitumor immune responses.

Sahin Ilyas I Eturi Aditya A De Souza Andre A Pamarthy Sahithi S Tavora Fabio F Giles Francis J FJ Carneiro Benedito A BA

Cancer biology & therapy 20190412 8

As a kinase at the crossroads of numerous metabolic and cell growth signaling pathways, glycogen synthase kinase-3 beta (GSK-3β) is a highly desirable therapeutic target in cancer. Despite its involvement in pathways associated with the pathogenesis of several malignancies, no selective GSK-3β inhibitor has been approved for the treatment of cancer. The regulatory role of GSK-3β in apoptosis, cell cycle, DNA repair, tumor growth, invasion, and metastasis reflects the therapeutic relevance of thi ...[more]

PMID: 30975030

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Project description:Background & aimsGlycogen synthase kinase 3β (Gsk3β [Gsk3b]) is a ubiquitously expressed kinase with distinctive functions in different types of cells. Although its roles in regulating innate immune activation and ischaemia and reperfusion injuries (IRIs) have been well documented, the underlying mechanisms remain ambiguous, in part because of the lack of cell-specific tools in vivo.MethodsWe created a myeloid-specific Gsk3b knockout (KO) strain to study the function of Gsk3β in macrophages in a murine liver partial warm ischaemia model.ResultsCompared with controls, myeloid Gsk3b KO mice were protected from IRI, with diminished proinflammatory but enhanced anti-inflammatory immune responses in livers. In bone marrow-derived macrophages, Gsk3β deficiency resulted in an early reduction of Tnf gene transcription but sustained increase of Il10 gene transcription on Toll-like receptor 4 stimulation in vitro. These effects were associated with enhanced AMP-activated protein kinase (AMPK) activation, which led to an accelerated and higher level of induction of the novel innate immune negative regulator small heterodimer partner (SHP [Nr0b2]). The regulatory function of Gsk3β on AMPK activation and SHP induction was confirmed in wild-type bone marrow-derived macrophages with a Gsk3 inhibitor. Furthermore, we found that this immune regulatory mechanism was independent of Gsk3β Ser9 phosphorylation and the phosphoinositide 3-kinase-Akt signalling pathway. In vivo, myeloid Gsk3β deficiency facilitated SHP upregulation by ischaemia-reperfusion in liver macrophages. Treatment of Gsk3b KO mice with either AMPK inhibitor or SHP small interfering RNA before the onset of liver ischaemia restored liver proinflammatory immune activation and IRI in these otherwise protected hosts. Additionally, pharmacological activation of AMPK protected wild-type mice from liver IRI, with reduced proinflammatory immune activation. Inhibition of the AMPK-SHP pathway by liver ischaemia was demonstrated in tumour resection patients.ConclusionsGsk3β promotes innate proinflammatory immune activation by restraining AMPK activation.Lay summaryGlycogen synthase kinase 3β promotes macrophage inflammatory activation by inhibiting the immune regulatory signalling of AMP-activated protein kinase and the induction of small heterodimer partner. Therefore, therapeutic targeting of glycogen synthase kinase 3β enhances innate immune regulation and protects liver from ischaemia and reperfusion injury.

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Glycogen synthase kinase-3 beta inhibitors as novel cancer treatments and modulators of antitumor immune responses.

Publications

Glycogen synthase kinase-3 beta inhibitors as novel cancer treatments and modulators of antitumor immune responses.

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