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.

Keywords: Cancer; GSK3β; invasion; therapeutic target; therapy resistance.

Figure 1

(a) Comparison of the structural and functional domains of the two GSK3 isoforms, (b) the sites (S9 and Y216) of phosphorylation of GSK3β by different kinases regulating GSK3β activity, and (c) the substrates of GSK3β and proteins that interact with it. (a) GSK3α (51 kD) and GSK3β (47 kD) are products of their respective genes located in chromosomes 19q13 and 3q13. The isoforms share high (98%) homology of the catalytic domains, and GSK3α has a glycine‐rich extension at the N‐terminal side. Blue and red narrow columns indicate the sites of serine (S) and tyrosine (Y) phosphorylation, respectively. (b) The kinases indicated in blue phosphorylate GSK3β‐S9 resulting in its inactivation, while those indicated in red phosphorylate GSK3β‐Y216 resulting in its activation. (c) GSK3β stabilizes/activates (red arrows) and destabilizes/inactivates (blue lines) various transcription factors as well as structural and functional proteins. AP‐1, activator protein 1; APC, adenomatous polyposis coli; BAX, BCL2‐associated X protein; BCL, B‐cell lymphoma; C, C‐terminal of protein; C/EBP, CCAAT (cytosine‐cytosine‐adenosine‐adenosine‐thymidine)‐enhancer‐binding protein; cdc25A, cell division cycle 25 homolog A; CREB, cAMP (cyclic adenosine monophosphate) response element binding protein; CRMP2, collapsin response mediator protein 2; eIF2B, eukaryotic initiation factor 2B; FAK, focal adhesion kinase; FGD‐1/3, FYVE RhoGEF (guanine nucleotide exchange factor) and PH domain‐containing protein 1/3; FKHR, forkhead in rhabdomyosarcoma; Gly, glycine; GR, glucocorticoid receptor; GS, glycogen synthase; GSK3β, glycogen synthase kinase 3β; HIF‐1α, hypoxia inducible factor‐1α; HSF‐1, heat shock transcription factor‐1; ILK, integrin‐linked kinase; IPF1/PDX1, insulin promoter factor 1/pancreatic and duodenal homeobox 1; IRS1, insulin receptor substrate 1; LRP5/6, lipoprotein receptor‐related protein 5/6; MafA, musculoaponeurotic fibrosarcoma oncogene homolog A; MAP1B/2C, microtubule associated protein 1B/2C; Mcl1, myeloid cell leukemia 1; mCRY2, mouse cryptochrom 2; MDM2, mouse double minute 2 homolog; MEK, MAPK (mitogen‐activated protein kinase)/ERK (extracellular signal‐regulated kinase) kinase; MITF, microphthalmia‐associated transcription factor; MLK3, mixed lineage kinase 3; N, N‐terminal of protein; NAC‐α, nascent polypeptide‐associated complex subunit‐α; NF‐AT, nuclear factor of activated T‐cells; NF‐κB, nuclear factor‐κB; Nrf2, nuclear factor erythroid 2‐related factor 2; p130RB, p130 retinoblastoma; p21CIP1, p21 CDK (cyclin‐dependent kinase)‐interacting protein 1; p90RSK, p90 ribosomal protein S6 kinase; PDH, pyruvate dehydrogenase; PKA, protein kinase A; PKC, protein kinase C; PP2A, protein phosphatase 2A; PPAR, peroxisome proliferator‐activated receptor; PTEN, phosphatase and tensin homolog; Pyk‐2, proline‐rich tyrosine kinase 2; RAR, retinoic acid receptor; Red1, RNA‐editing deaminase 1; S, serine; SRC‐3, steroid receptor coactivator‐3; SREBP, sterol regulatory element‐binding protein; TSC2, tuberous sclerosis complex 2; VDAC, voltage‐dependent anion channel; Y, tyrosine

Figure 2

Putative molecular pathway through which deregulated GSK3β promotes tumor cell migration and invasion. The exact molecular pathway by which GSK3β mediates the activation of FAK (open arrow) remains to be determined. FAK, focal adhesion kinase; GDP, guanosine diphosphate; GEF, guanine nucleotide exchange factor; GSK3β, glycogen synthase kinase 3β; GTP, guanosine triphosphate; JNK, c‐Jun N‐terminal kinase; MMP, matrix metalloproteinase; MT1‐MMP, membrane type 1‐MMP; circled P, phosphorylation.

Figure 3

(a) Putative molecular pathway that links GSK3β activity with the resistance of pancreatic cancer cells to DNA damage induced by gemcitabine and ionizing radiation. The effects of GSK3β on E2F‐dependent gene transcription and on the expression of RR, TS and TK remain to be determined. CDK, cyclin‐dependent kinase; E2F, E2 factor; circled P, phoshorylation; Rb, retinoblastoma (tumor suupressor protein); RR, ribonucleotide reductase; TK, thymidine kinase; TS, thymidylate synthase. (b) Regulation of MGMT expression by GSK3β signaling in glioblastoma. GSK3β inhibition results in c‐Myc activation directly and via activation of β‐catenin‐mediated signaling, which consequently increases recruitment of DNMT3A by c‐Myc to the MGMT promoter, thus increasing de novo DNA methylation in the MGMT promoter. The methylated status of the MGMT promoter increases the sensitivity of glioblastoma to temozolomide. DNMT3A, DNA (cytosine‐5)‐methyltransferase 3A; MGMT, O⁶‐methylguanine DNA methyltransferase.

Figure 4

Involvement of GSK3β in the representative pathological hallmarks of cancer. GSK3β positively regulates the distinct molecular pathways and participates in survival, proliferation, migration and invasion of tumor cells and their insensitivity and resistance to cancer therapy. The cancer stemness phenotypes might underlie the process of these pathological hallmarks. Abbreviations are defined in Figures 1, 2 and 3.