Targeting PRMT5/Akt signalling axis prevents human lung cancer cell growth

Zhang, Shikui; Ma, Yaqiong; Hu, Xiaoyan; Zheng, Yonghua; Chen, Xiaoke

doi:10.1111/jcmm.14036

Cited by 45 publications

(55 citation statements)

References 20 publications

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“…Hence, this data highly suggest PRMT5 to be an upstream regulator of AKT signaling. Recently, PRMT5 has been reported to directly colocalize and interact with AKT in lung cancer cells, but it did not influence PTEN or mTOR (48).…”

Section: Discussionmentioning

confidence: 93%

Selective PRMT5 Inhibitors Suppress Human CD8+ T Cells by Upregulation of p53 and Impairment of the AKT Pathway Similar to the Tumor Metabolite MTA

Strobl

Schaffer

Haug

et al. 2020

Molecular Cancer Therapeutics

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Genetic alterations in tumor cells provide promising targets for antitumor therapy. Recently, loss of methylthioadenosine phosphorylase (MTAP), a deletion frequently occurring in cancer, has been shown to create vulnerability to the inhibition of the protein arginine methyltransferase 5 (PRMT5). MTAP deficiency leads to accumulation of methylthioadenosine (MTA), which reduces PRMT5 activity, and thus, sensitizes the tumor cells to selective PRMT5 inhibitors (PRMT5i). PRMT5i are investigated as a new strategy to selectively kill MTAP-deficient tumor cells by blocking residual PRMT5 activity, but also to treat PRMT5-overexpressing tumors. Although many studies investigated the role of PRMT5 in cancer, only little data exist about the effect of PRMT5 inhibition on immune cells. As we could show that the tumor metabolite MTA suppresses T cells, we asked whether selective PRMT5 inhibition is detrimental for T-cell immune responses. Therefore, we examined the effect of the synthetic PRMT5 inhibitor EPZ015666 on human CD8 þ T cells in direct comparison with the naturally occurring PRMT5-inhibiting molecule MTA. Both compounds reduced T-cell proliferation, viability, and functionality. In addition, T-cell metabolism was impaired upon PRMT5 inhibition. These effects coincided with the induction of p53 expression and reduced AKT/mTOR signaling. Our data clearly demonstrate that PRMT5 activity is involved in various cellular processes of human CD8 þ T cells associated with essential T-cell functions. Therefore, not only tumor cells, but also antitumor immune responses, are compromised by PRMT5 inhibitors. This emphasizes the importance of considering side effects on the immune system when developing new strategies to specifically target not only MTAP-deficient tumors.

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Section: Discussionmentioning

confidence: 93%

Selective PRMT5 Inhibitors Suppress Human CD8+ T Cells by Upregulation of p53 and Impairment of the AKT Pathway Similar to the Tumor Metabolite MTA

Strobl

Schaffer

Haug

et al. 2020

Molecular Cancer Therapeutics

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“…Previous studies have shown that Akt, also named PKB, was involved in cancer cell growth and tumor progression. Recently, several studies reported that PRMT5 interacted and regulated Akt activation in mouse liver cells 2 , lung cancer cells 7 , and lymphoma cells 13 . Nevertheless, it is still unclear whether PRMT5 promotes lung cancer cell death and chemosensitivity via regulation of Akt activity upon resveratrol treatment.…”

Section: Resultsmentioning

confidence: 99%

“…Recent studies have shown that PRMT5 interacted with Akt and regulated Akt activation, which controlled cancer cell replication and growth 7 . Moreover, Akt is activated by PRMT5 through hyperphosphorylation of PI3-K and hypophosphorylation of PTEN 12 and co-localization of Akt 7 . These investigations mainly focused on the relationship between PRMT5 and Akt and related mechanisms.…”

Section: Discussionmentioning

confidence: 99%

PRMT5 Promotes Human Lung Cancer Cell Apoptosis via Akt/Gsk3β Signaling Induced by Resveratrol

Yang

et al. 2019

Cell Transplant

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Protein arginine methyltransferase 5 (PRMT5) is implicated in various types of human cancer and tumor development, especially in lung cancer. Nevertheless, it is still unclear whether suppression of PRMT5 could promote lung cancer cell apoptosis and chemosensitivity induced by resveratrol, and the underlying molecular mechanism remains completely unknown. Here, we showed that PRMT5 was overexpressed in human lung cancer tissues and different types of lung cancer cell lines. Moreover, we constructed PRMT5 stable knockdown cell lines (A549 and ASCT-a-1) and investigated the roles of PRMT5 and the related signaling pathway in lung cancer cell apoptosis induced by resveratrol. Our results indicated that inhibition or down-regulation of PRMT5 by GSK591, a PRMT5-specific inhibitor, or shRNAs markedly enhanced cell apoptosis and chemosensitivity stimulated by resveratrol. Further investigation showed that inhibition or down-regulation of PRMT5 further reduced Akt/GSK3β phosphorylation and the downstream targets cyclin D1 and E1 expression upon resveratrol treatment. Our findings suggest that PRMT5 is a pivotal mediator for human lung cancer cell death induced by resveratrol, which also reveals that PRMT5 may serve as a new therapeutic target for the treatment of human lung cancer.

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“…Especially in lung cancer cells, PRMT5 was proved to promote cell proliferation through direct interaction with Akt and regulation of Akt activity. 21 More recently, PRMT5 was demonstrated that lead to FBW7 expression to promote tumorigenesis in pancreatic cancer. 14 ling, 24 and EGF-induced nuclear translocation of SHCBP1 directly increased acetylation of β-catenin to enhanced NSCLC cellular stemness, 25 which is suggested that EGFR signalling can drive β-catenin activation via various routes.…”

Section: Discussionmentioning

confidence: 99%

PRMT5 promotes epithelial‐mesenchymal transition via EGFR‐β‐catenin axis in pancreatic cancer cells

Wang

et al. 2019

J Cellular Molecular Medi

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Protein arginine methyltransferase 5 (PRMT5) has been implicated in the development and progression of human cancers. However, few studies reveal its role in epithelial-mesenchymal transition (EMT) of pancreatic cancer cells. In this study, we find that PRMT5 is up-regulated in pancreatic cancer, and promotes proliferation, migration and invasion in pancreatic cancer cells, and promotes tumorigenesis. Silencing PRMT5 induces epithelial marker E-cadherin expression and down-regulates expression of mesenchymal markers including Vimentin, collagen I and β-catenin in PaTu8988 and SW1990 cells, whereas ectopic PRMT5 re-expression partially reverses these changes, indicating that PRMT5 promotes EMT in pancreatic cancer.More importantly, we find that PRMT5 knockdown decreases the phosphorylation level of EGFR at Y1068 and Y1172 and its downstream p-AKT and p-GSK3β, and then results in down-regulation of β-catenin. Expectedly, ectopic PRMT5 re-expression also reverses the above changes. It is suggested that PRMT5 promotes EMT probably via EGFR/AKT/β-catenin pathway. Taken together, our study demonstrates that PRMT5 plays oncogenic roles in the growth of pancreatic cancer cell and provides a potential candidate for pancreatic cancer treatment. K E Y W O R D SAKT, EGFR, epithelial-mesenchymal transition, GSK3β, protein arginine methyltransferase 5, β-catenin

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Targeting PRMT5/Akt signalling axis prevents human lung cancer cell growth

Cited by 45 publications

References 20 publications

Selective PRMT5 Inhibitors Suppress Human CD8+ T Cells by Upregulation of p53 and Impairment of the AKT Pathway Similar to the Tumor Metabolite MTA

Selective PRMT5 Inhibitors Suppress Human CD8+ T Cells by Upregulation of p53 and Impairment of the AKT Pathway Similar to the Tumor Metabolite MTA

PRMT5 Promotes Human Lung Cancer Cell Apoptosis via Akt/Gsk3β Signaling Induced by Resveratrol

PRMT5 promotes epithelial‐mesenchymal transition via EGFR‐β‐catenin axis in pancreatic cancer cells

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