GSK-3 Promotes Cell Survival, Growth, and PAX3 Levels in Human Melanoma Cells

Kubic, Jennifer D.; Mascarenhas, Joseph B.; Iizuka, Takumi; Wolfgeher, Don; Lang, Deborah

doi:10.1158/1541-7786.mcr-11-0387

Cited by 31 publications

(22 citation statements)

References 47 publications

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“…On the other hand, GSK is a constitutively active serine/threonine kinase that plays a role in the Wnt/β‐catenin pathway where it negatively regulates β‐catenin in unstimulated cells . Phosphorylation of GSK 3α‐β leads to its inhibition and results in the induction of apoptosis in melanoma cells . When PI3K/AKT is the dominant survival pathway, apoptosis induced by PI3K/AKT inhibition is attenuated by the DHT treatment .…”

Section: Discussionmentioning

confidence: 99%

A natural molecule, urolithin A, downregulates androgen receptor activation and suppresses growth of prostate cancer

Dahiya

Chandrasekaran

Kolluru

et al. 2018

Molecular Carcinogenesis

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Androgen ablation therapy is the primary therapeutic option for locally advanced and metastatic castration-resistant prostate cancer (CRPC). We investigated therapeutic effect of a dietary metabolite Urolithin A (UroA) and dissected the molecular mechanism in CRPC cells. Treatment with UroA inhibited cell proliferation in both androgen receptor-positive (AR ) (C4-2B) and androgen receptor-negative (AR ) (PC-3) cells however, AR CaP cells were more sensitive to UroA treatment as compared with AR CaP cells. Inhibition of the AR signaling was responsible for the UroA effect on AR CaP cells. Ectopic expression of AR in PC-3 cells sensitized them to UroA treatment as compared to the vector-expresseing PC-3 cells, which suggests that AR could be a target of UroA. Similarly, in enzalutamide-resistant C4-2B cells, a downregulation of AR expression also suppressed cell proliferation which was observed with the UroA treatment. Oral administration of UroA significantly suppressed the growth of C4-2B xenografts (P = 0.05) compared with PC-3 xenografts (P = 0.069) without causing toxicity to animals. Immunohistochemistry analysis confirmed in vitro findings such as downregulation of AR/pAKT signaling in UroA-treated C4-2B tumors, which suggests that UroA may be a potent chemo-preventive and therapeutic agent for CRPC.

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Section: Discussionmentioning

confidence: 99%

A natural molecule, urolithin A, downregulates androgen receptor activation and suppresses growth of prostate cancer

Dahiya

Chandrasekaran

Kolluru

et al. 2018

Molecular Carcinogenesis

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“…Among the nine numbers of PAX genes, PAX3 was characterized as a cancer promoting gene, acting as a mediator of tumor progression and a marker of unfavorable outcome . It is well documented that PAX3 plays an essential role in differentiation and migration of muscle precursor cells and neural crest cells, thus it is often implicated in the tumorigenesis of these tissues, including rhabdomyosarcoma , glioma , melanoma , and neuroblastoma . However, the expression and roles of PAX3 in OS have not been elucidated.…”

Section: Discussionmentioning

confidence: 99%

Loss of MicroRNA‐489‐3p promotes osteosarcoma metastasis by activating PAX3‐MET pathway

Liu

Yang

Qian

2016

Molecular Carcinogenesis

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Osteosarcoma (OS) remains one deadly disease for many affected patients. MicroRNAs (miRNAs) are thought to have an important role in tumor metastasis by regulating diverse cellular pathways. Here, we describe the function and regulation network of miR-489-3p in osteosarcoma (OS) metastasis. MiR-489-3p expression was downregulated in OS cells especially in high metastatic potential cells and was also significantly decreased in metastatic lesions compared with their corresponding primary tumor samples. Both gain- and loss-of-function studies confirmed that miR-489-3p significantly suppressed OS cell invasion and metastasis both in vitro and in vivo. Mechanistically, paired box gene 3 (PAX3) was identified as a functional target of miR-489-3p in OS cells. MiR-489-3p inhibited OS metastasis by negatively regulating expression of PAX3. In addition, PAX3 expression was markedly higher in OS tissues than in adjacent non-cancerous tissues. Transwell assays and in vivo metastasis assays demonstrated that overexpression of PAX3 significantly promoted the invasiveness and pulmonary metastasis of OS cells. On the other hand, downregulation of PAX3 markedly reduced cell metastatic potential. Mechanistic investigations indicated that prometastasis function of PAX3 was mediated by upregulating downstream target MET tyrosine kinase receptor. In conclusion, our results reveal that miR-489-3p-PAX3-MET signaling is critical to OS metastasis. Targeting the pathway described here may open new therapeutic prospects to restrict the metastatic potential of OS. © 2016 Wiley Periodicals, Inc.

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“…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.…”

Section: Introductionmentioning

confidence: 99%

Molecular Pathways: Revisiting Glycogen Synthase Kinase-3β as a Target for the Treatment of Cancer

Walz

Ugolkov

Chandra³

et al. 2017

Clinical Cancer Research

124

102

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Glycogen synthase kinase-3β (GSK-3β), a serine/threonine protein kinase, is a complex regulator of numerous cellular functions. GSK-3β is a unique kinase which is constitutively active in resting and non-stimulated cells. GSK-3β has been implicated in a wide range of diseases including neurodegeneration, inflammation and fibrosis, noninsulin-dependent diabetes mellitus, and cancer. It is a regulator of NF-κB-mediated survival of cancer cells, which provided a rationale for the development of GSK-3 inhibitors targeting malignant tumors. Recent studies, many of them reported over the past decade, have identified GSK-3β as a potential therapeutic target in at over 15 different types of cancer. Whereas only active GSK-3β is expressed in cancer cell nucleus, aberrant nuclear accumulation of GSK-3β has been identified as a hallmark of cancer cells in malignant tumors of different origin. This review focuses on the preclinical and clinical development of GSK-3 inhibitors, and the potential therapeutic impact of targeting GSK-3β in human cancer.

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GSK-3 Promotes Cell Survival, Growth, and PAX3 Levels in Human Melanoma Cells

Cited by 31 publications

References 47 publications

A natural molecule, urolithin A, downregulates androgen receptor activation and suppresses growth of prostate cancer

A natural molecule, urolithin A, downregulates androgen receptor activation and suppresses growth of prostate cancer

Loss of MicroRNA‐489‐3p promotes osteosarcoma metastasis by activating PAX3‐MET pathway

Molecular Pathways: Revisiting Glycogen Synthase Kinase-3β as a Target for the Treatment of Cancer

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