GSK-3β in Pancreatic Cancer: Spotlight on 9-ING-41, Its Therapeutic Potential and Immune Modulatory Properties

Park, Robin; Coveler, Andrew L.; Cavalcante, Ludimila; Saeed, Anwaar

doi:10.3390/biology10070610

Cited by 14 publications

(17 citation statements)

References 84 publications

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“…However, the molecular mechanisms underlying this effect are still awaiting clarification, although GSK-3β has been shown to bind to centrosomes and mitotic spindles in lymphoma cells [ 170 ]. These findings, along with those from other investigators [ 171 ], have paved the groundwork for a phase 1 trial of 9-ING-41 (NCT03678883), which is currently underway [ 172 ].…”

Section: Gsk-3 Signaling In B-cell Nhlsmentioning

confidence: 77%

Pathobiology and Therapeutic Relevance of GSK-3 in Chronic Hematological Malignancies

Martelli

Paganelli

Evangelisti

et al. 2022

Cells

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Glycogen synthase kinase-3 (GSK-3) is an evolutionarily conserved, ubiquitously expressed, multifunctional serine/threonine protein kinase involved in the regulation of a variety of physiological processes. GSK-3 comprises two isoforms (α and β) which were originally discovered in 1980 as enzymes involved in glucose metabolism via inhibitory phosphorylation of glycogen synthase. Differently from other proteins kinases, GSK-3 isoforms are constitutively active in resting cells, and their modulation mainly involves inhibition through upstream regulatory networks. In the early 1990s, GSK-3 isoforms were implicated as key players in cancer cell pathobiology. Active GSK-3 facilitates the destruction of multiple oncogenic proteins which include β-catenin and Master regulator of cell cycle entry and proliferative metabolism (c-Myc). Therefore, GSK-3 was initially considered to be a tumor suppressor. Consistently, GSK-3 is often inactivated in cancer cells through dysregulated upstream signaling pathways. However, over the past 10–15 years, a growing number of studies highlighted that in some cancer settings GSK-3 isoforms inhibit tumor suppressing pathways and therefore act as tumor promoters. In this article, we will discuss the multiple and often enigmatic roles played by GSK-3 isoforms in some chronic hematological malignancies (chronic myelogenous leukemia, chronic lymphocytic leukemia, multiple myeloma, and B-cell non-Hodgkin’s lymphomas) which are among the most common blood cancer cell types. We will also summarize possible novel strategies targeting GSK-3 for innovative therapies of these disorders.

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Section: Gsk-3 Signaling In B-cell Nhlsmentioning

confidence: 77%

Pathobiology and Therapeutic Relevance of GSK-3 in Chronic Hematological Malignancies

Martelli

Paganelli

Evangelisti

et al. 2022

Cells

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“…Notably, GSK-3β itself participates in cell proliferation, apoptosis, cell cycle progression and cell signal transduction (45)(46)(47). As a serine-threonine kinase, GSK-3β can exert tumor-promoter and tumor-suppressor effects by phosphorylating a broad range of substrates (48,49).…”

Section: Discussionmentioning

confidence: 99%

Long non‑coding RNA 01614 hyperactivates WNT/β‑catenin signaling to promote pancreatic cancer progression by suppressing GSK‑3β

Chen

Wang

et al. 2022

Int J Oncol

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Pancreatic cancer (PC) is a lethal type of cancer for which effective therapies are limited. Long non-coding RNAs (lncRNAs) represent a critical type of regulator category, mediating the tumorigenesis and development of various tumor types, including PC. However, the expression patterns and functions of numerous lncRNAs in PC remain poorly understood. In the present study, linc01614 was identified as a PC-related lncRNA. linc01614 was notably upregulated in PC tissues and cell lines and was associated with the poor disease-free survival of patients with PC according to the analysis of The Cancer Genome Atlas-derived datasets. Functionally, linc01614 knockdown suppressed PC cell proliferation, migration and invasion in vitro, and inhibited tumor proliferation in vitro and in vivo. Mechanistically, linc01614 overexpression stabilized the level of β-catenin protein to hyperactivate the WNT/β-catenin signaling pathway in PC cells. Further analyses revealed that linc01614 bound to GSK-3β and perturbed the interaction between GSK-3β and AXIN1, thereby preventing the formation of the β-catenin degradation complex and reducing the degradation of β-catenin. In summary, the present findings reveal that linc01614 may function as an oncogene and promote the progression of PC and may thus be considered as a potential therapeutic target in the future.

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“…Glycogen synthase kinase 3 (GSK-3) is a ubiquitously expressed serine/threonine kinase and protooncogene ( 92 , 93 ). GSK-3 has two isoforms, GSK-3α and GSK-3β, which have homologous kinase domains but divergent C-terminal domains, as well as non-redundant functionality ( 94 ).…”

Section: Gsk-3mentioning

confidence: 99%

“…For example, in non-small cell lung cancer (NSCLC), GSK-3b expression is associated with cervical lymph node metastases, poor differentiation, advanced stage, late diagnosis, and worse survival, while inhibiting GSK-3 can result in cancer cell apoptosis and cell cycle arrest (99,100). In vivo models of pancreatic cancer demonstrate an inverse relationship between survival and the nuclear amount of aberrant GSK-3 (93). GSK-3 inhibition in mice by knockout or small molecule inhibitors increases cytotoxicity against viral infections and tumor cell models of gastric cancer (MFC), melanoma (B16), lymphoma (EL-4), colon cancer (MC38), colorectal cancer (CT26), pancreatic cancer (KPC), and lung cancer (LLC) (94,(101)(102)(103)(104).…”

Section: Tumor Cellsmentioning

confidence: 99%

Combination Approaches to Target PD-1 Signaling in Cancer

2022

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Cancer remains the second leading cause of death in the US, accounting for 25% of all deaths nationwide. Immunotherapy techniques bolster the immune cells’ ability to target malignant cancer cells and have brought immense improvements in the field of cancer treatments. One important inhibitory protein in T cells, programmed cell death protein 1 (PD-1), has become an invaluable target for cancer immunotherapy. While anti-PD-1 antibody therapy is extremely successful in some patients, in others it fails or even causes further complications, including cancer hyper-progression and immune-related adverse events. Along with countless translational studies of the PD-1 signaling pathway, there are currently close to 5,000 clinical trials for antibodies against PD-1 and its ligand, PD-L1, around 80% of which investigate combinations with other therapies. Nevertheless, more work is needed to better understand the PD-1 signaling pathway and to facilitate new and improved evidence-based combination strategies. In this work, we consolidate recent discoveries of PD-1 signaling mediators and their therapeutic potential in combination with anti-PD-1/PD-L1 agents. We focus on the phosphatases SHP2 and PTPN2; the kinases ITK, VRK2, GSK-3, and CDK4/6; and the signaling adaptor protein PAG. We discuss their biology both in cancer cells and T cells, with a focus on their role in relation to PD-1 to determine their potential in therapeutic combinations. The literature discussed here was obtained from a search of the published literature and ClinicalTrials.gov with the following key terms: checkpoint inhibition, cancer immunotherapy, PD-1, PD-L1, SHP2, PTPN2, ITK, VRK2, CDK4/6, GSK-3, and PAG. Together, we find that all of these proteins are logical and promising targets for combination therapy, and that with a deeper mechanistic understanding they have potential to improve the response rate and decrease adverse events when thoughtfully used in combination with checkpoint inhibitors.

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GSK-3β in Pancreatic Cancer: Spotlight on 9-ING-41, Its Therapeutic Potential and Immune Modulatory Properties

Cited by 14 publications

References 84 publications

Pathobiology and Therapeutic Relevance of GSK-3 in Chronic Hematological Malignancies

Pathobiology and Therapeutic Relevance of GSK-3 in Chronic Hematological Malignancies

Long non‑coding RNA 01614 hyperactivates WNT/β‑catenin signaling to promote pancreatic cancer progression by suppressing GSK‑3β

Combination Approaches to Target PD-1 Signaling in Cancer

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