Is p38γ MAPK a metastasis-promoting gene or an oncogenic property-maintaining gene?

Meng, Fanyan; Wu, Guojun

doi:10.4161/cc.25333

Cited by 8 publications

(6 citation statements)

References 5 publications

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“…Recently, p38γ MAPK has emerged as an oncogenic MAPK (MAPK) [2–6]. It was also found to be highly expressed in some human cancer cells [4, 5, 7, 8].…”

Section: Introductionmentioning

confidence: 99%

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Role of p38γ MAPK in regulation of EMT and cancer stem cells

Wang

et al. 2018

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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p38γ is a member of p38 MAPK family which contains four isoforms p38α, p38β, p38γ, and p38δ. p38γ MAPK has unique function and is less investigated. Recent studies revealed that p38γ MAPK may be involved in tumorigenesis and cancer aggressiveness. However, the underlying cellular/molecular mechanisms remain unclear. Epithelial-mesenchymal transition (EMT) is a process that epithelial cancer cells transform to facilitate the loss of epithelial features and gain of mesenchymal phenotype. EMT promotes cancer cell progression and metastasis, and is involved in the regulation of cancer stem cells (CSCs) which have self-renewal capacity and are resistant to chemotherapy and target therapy. We showed that p38γ MAPK significantly increased EMT in breast cancer cells; over-expression of p38γ MAPK enhanced EMT while its down-regulation inhibited EMT. Meanwhile, p38γ MAPK augmented CSC population while knock down of p38γ MAPK decreased CSC ratio in breast cancer cells. MicroRNA-200b (miR-200b) was down-stream of p38γ MAPK and inhibited by p38γ MAPK; miR-200b mimics blocked p38γ MAPK-induced EMT while miR-200b inhibitors promoted EMT. p38γ MAPK regulated miR-200b through inhibiting GATA3. p38γ MAPK induced GATA3 ubiquitination, leading to its proteasome-dependent degradation. Suz12, a Polycomb group protein, was down-stream of miR-200b and involved in miR-200b regulation of EMT. Thus, our study established an important role of p38γ MAPK in EMT and identified a novel signaling pathway for p38γ MAPK-mediated tumor promotion.

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“…Recently, p38γ MAPK has emerged as an oncogenic MAPK (MAPK) [2–6]. It was also found to be highly expressed in some human cancer cells [4, 5, 7, 8].…”

Section: Introductionmentioning

confidence: 99%

“…It was also found to be highly expressed in some human cancer cells [4, 5, 7, 8]. p38γ MAPK is shown to be involved in the regulation of cancer stem cells (CSCs), migration/invasion, tumorigenesis, and cell transformation [2–6, 9, 10]. However, the underlying mechanisms and cell signaling pathways are unclear.…”

Section: Introductionmentioning

confidence: 99%

Role of p38γ MAPK in regulation of EMT and cancer stem cells

Wang

et al. 2018

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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“…P38 mitogen‐activated protein kinases are a class of mitogen‐activated protein kinases that are responsive to stress stimuli, such as heat and osmotic shock, cytokines, and UV irradiation, and they are involved in cell differentiation, autophagy, and apoptosis. Four p38 MAP kinases, p38α (MAPK14), β (MAPK11), γ (MAPK12/ERK6), and δ (MAPK13/SAPK4), have been identified, and their functions in cancer remain elusive (Meng & Wu, 2013). The p38 pathway has been most frequently associated with a tumor suppressor function by negatively regulating cell survival and proliferation (Han & Sun, 2007).…”

Section: Resultsmentioning

confidence: 99%

NRAS^Q61K melanoma tumor formation is reduced by p38‐MAPK14 activation in zebrafish models and NRAS‐mutated human melanoma cells

Banik

Cheng

Dooley

et al. 2020

Pigment Cell Melanoma Res

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Oncogenic BRAF and NRAS mutations drive human melanoma initiation. We used transgenic zebrafish to model NRAS‐mutant melanoma, and the rapid tumor onset allowed us to study candidate tumor suppressors. We identified P38α‐MAPK14 as a potential tumor suppressor in The Cancer Genome Atlas melanoma cohort of NRAS‐mutant melanomas, and overexpression significantly increased the time to tumor onset in transgenic zebrafish with NRAS‐driven melanoma. Pharmacological activation of P38α‐MAPK14 using anisomycin reduced in vitro viability of melanoma cultures, which we confirmed by stable overexpression of p38α. We observed that the viability of MEK inhibitor resistant melanoma cells could be reduced by combined treatment of anisomycin and MEK inhibition. Our study demonstrates that activating the p38α‐MAPK14 pathway in the presence of oncogenic NRAS abrogates melanoma in vitro and in vivo. Significance The significance of our study is in the accountability of NRAS mutations in melanoma. We demonstrate here that activation of p38α‐MAPK14 pathway can abrogate NRAS‐mutant melanoma which is contrary to the previously published role of p38α‐MAPK14 pathway in BRAF mutant melanoma. These results implicate that BRAF and NRAS‐mutant melanoma may not be identical biologically. We also demonstrate the translational benefit of our study by using a small molecule compound‐anisomycin (already in use for other diseases in clinical trials) to activate p38α‐MAPK14 pathway.

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“…PLK1-based therapies have led to the simultaneous identification of a number of dual-targeting inhibitors. ,− ,, These compounds offer the advantage of a wider range of drug applications for multiple tumor entities and show reduced risk for developing resistance during treatment . Meanwhile, the p38γ, a member of the p38 MAPK family, has emerged as a potential therapeutic target for a variety of cancers. , p38γ is required for the normal kinetochore localization of PLK1, and PLK1 also was reported as mitotic substrate of the p38 MAPK pathway . Recently, one study found that activation of p38 MAPK can be triggered by PLK1 inhibition .…”

Section: Discussionmentioning

confidence: 99%

Combination of QSAR Modeling and Hybrid-Based Consensus Scoring to Identify Dual-Targeting Inhibitors of PLK1 and p38γ

Cheng,

Hwang,

Bhave

et al. 2023

J. Chem. Inf. Model.

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Polo-like kinase 1 (PLK1) and p38γ mitogen-activated protein kinase (p38γ) play important roles in cancer pathogenesis by controlling cell cycle progression and are therefore attractive cancer targets. The design of multitarget inhibitors may offer synergistic inhibition of distinct targets and reduce the risk of drug−drug interactions to improve the balance between therapeutic efficacy and safety. We combined deep-learning-based quantitative structure−activity relationship (QSAR) modeling and hybrid-based consensus scoring to screen for inhibitors with potential activity against the targeted proteins. Using this combination strategy, we identified a potent PLK1 inhibitor (compound 4) that inhibited PLK1 activity and liver cancer cell growth in the nanomolar range. Next, we deployed both our QSAR models for PLK1 and p38γ on the Enamine compound library to identify dual-targeting inhibitors against PLK1 and p38γ. Likewise, the identified hits were subsequently subjected to hybrid-based consensus scoring. Using this method, we identified a promising compound (compound 14) that could inhibit both PLK1 and p38γ activities. At nanomolar concentrations, compound 14 inhibited the growth of human hepatocellular carcinoma and hepatoblastoma cells in vitro. This study demonstrates the combined screening strategy to identify novel potential inhibitors for existing targets.

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Is p38γ MAPK a metastasis-promoting gene or an oncogenic property-maintaining gene?

Cited by 8 publications

References 5 publications

Role of p38γ MAPK in regulation of EMT and cancer stem cells

Role of p38γ MAPK in regulation of EMT and cancer stem cells

NRAS^Q61K melanoma tumor formation is reduced by p38‐MAPK14 activation in zebrafish models and NRAS‐mutated human melanoma cells

Combination of QSAR Modeling and Hybrid-Based Consensus Scoring to Identify Dual-Targeting Inhibitors of PLK1 and p38γ

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Is p38γ MAPK a metastasis-promoting gene or an oncogenic property-maintaining gene?

Cited by 8 publications

References 5 publications

Role of p38γ MAPK in regulation of EMT and cancer stem cells

Role of p38γ MAPK in regulation of EMT and cancer stem cells

NRASQ61K melanoma tumor formation is reduced by p38‐MAPK14 activation in zebrafish models and NRAS‐mutated human melanoma cells

Combination of QSAR Modeling and Hybrid-Based Consensus Scoring to Identify Dual-Targeting Inhibitors of PLK1 and p38γ

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NRAS^Q61K melanoma tumor formation is reduced by p38‐MAPK14 activation in zebrafish models and NRAS‐mutated human melanoma cells