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

Abstract

Tumor cell invasion and resistance to therapy are the most intractable biological characteristics of cancer and, therefore, the most challenging for current cancer research and treatment paradigms. Refractory cancers, including pancreatic cancer and glioblastoma, show an inextricable association between the highly invasive behavior of tumor cells and their resistance to chemotherapy, radiotherapy and targeted therapies. These aggressive properties of cancer share distinct cellular pathways that are connected to each other by several molecular hubs. There is increasing evidence to show that glycogen synthase kinase (GSK)‐3β is aberrantly activated in various cancer types and this has emerged as a potential therapeutic target. In many but not all cancer types, aberrant GSK3β sustains the survival, immortalization, proliferation and invasion of tumor cells, while also rendering them insensitive or resistant to chemotherapeutic agents and radiation. Here we review studies that describe associations between therapeutic stimuli/resistance and the induction of pro‐invasive phenotypes in various cancer types. Such cancers are largely responsive to treatment that targets GSK3β. This review focuses on the role of GSK3β as a molecular hub that connects pathways responsible for tumor invasion and resistance to therapy, thus highlighting its potential as a major cancer therapeutic target. We also discuss the putative involvement of GSK3β in determining tumor cell stemness that underpins both tumor invasion and therapy resistance, leading to intractable and refractory cancer with dismal patient outcomes.

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

“…Its known functions and involvement in primary pathologies has established GSK3β as a therapeutic target for type 2 diabetes mellitus, neurodegenerative diseases and inflammation . Unlike its effects against several proto‐oncoproteins (eg, β‐catenin, cyclin D1) and mediators of epithelial‐mesenchymal transition (eg, snail) in untransformed cells, we previously reported that deregulated GSK3β facilitates the progression of gastrointestinal cancers, glioblastoma and osteosarcoma . This stems from the observation that GSK3β promotes tumor cell survival, proliferation and invasion by modulating distinct tumor suppressor and cell immortality pathways, as well as cell motility.…”

“…This stems from the observation that GSK3β promotes tumor cell survival, proliferation and invasion by modulating distinct tumor suppressor and cell immortality pathways, as well as cell motility. Moreover, GSK3β renders cancer cells insensitive to chemotherapeutics and ionizing radiation . Our observations and other studies establish GSK3β as a common and attractive therapeutic target for a broad spectrum of chronic diseases including cancer .…”

Resibufogenin suppresses transforming growth factor‐β‐activated kinase 1‐mediated nuclear factor‐κB activity through protein kinase C‐dependent inhibition of glycogen synthase kinase 3

“…A recent study suggested that GSK‐3 plays a critical role in maintaining constitutive NF‐κB activity and cell survival in cancer cells . In addition, inactivation of GSK‐3 has been shown to inhibit the growth of various cancers, including pancreatic cancer . Glycogen synthase kinase‐3 regulates growth and survival in pancreatic cancer cells by stabilizing the TAK1‐TAB complex to promote IKK activity and subsequent NF‐κB DNA binding and activity .…”

“…5 In addition, inactivation of GSK-3 has been shown to inhibit the growth of various cancers, including pancreatic cancer. [13][14][15] Glycogen synthase kinase-3 regulates growth and survival in pancreatic cancer cells by stabilizing the TAK1-TAB complex to promote IKK activity and subsequent NF-κB DNA binding and activity. 16,17 Moreover, it is reported that GSK-3 also plays an important role in promoting noncanonical NF-κB signaling in pancreatic cancer cells.…”

Ornithine aminotransferase promoted the proliferation and metastasis of non‐small cell lung cancer via upregulation of miR‐21

“…Based on the bioinformatics prediction, GSK-3β was one of the predicted targets of miR-21, GSK-3β was chosen for further investigation in our study due to the fact that GSK-3β is a pivotal mediator of cancer progression and resistance to therapy (Domoto et al, 2016;Walz et al, 2017). We demonstrated that GSK-3β was a direct target of miR-21 in NSCLC and activation of Wnt/β- β-catenin signaling components have been extensively reported in various diseases such as focal dermal hypoplasia, obesity, type II diabetes and different cancers (MacDonald, Tamai, & He, 2009;Wang et al, 2016;Xu et al, 2017).…”