Knockdown of growth differentiation factor-15 inhibited nonsmall cell lung cancer through inactivating PTEN/PI3K/AKT signaling pathway

Liu, Yongshi; Lei, Jie; Xiang, Ji; Li, Chunmei; Chen, Xiaoxia; Wang, Juan; Dong, Jiajia; Zhang, Hongpei; Li, Yan

doi:10.1007/s13258-022-01328-8

Cited by 6 publications

(5 citation statements)

References 31 publications

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“…Mechanistically, GDF15 inhibits apoptosis by promoting rapid and transient Ser473 phosphorylation (activation) of Akt and a subsequent increase in Ser136 phosphorylation (inactivation) of Bad, which is well known to promote apoptosis through the intrinsic mitochondrial pathway 43 . This finding was consistent with Liu et al's study showing that inhibition of GDF15 stabilized PTEN, in turn inactivating the PI3K/AKT pathway and finally inducing cancer cell apoptosis 44 . As expected, increased expression of GDF15 in B16F1 melanoma cells promoted tumor growth in the B16F1 melanoma mouse model 47 .…”

Section: Discussionsupporting

confidence: 92%

“…High GDF15 serum levels were also correlated with poorer overall survival in melanoma patients 41 . In addition, GDF15 has been extensively reported to act as an antiapoptotic protein [42][43][44][45][46] . Mechanistically, GDF15 inhibits apoptosis by promoting rapid and transient Ser473 phosphorylation (activation) of Akt and a subsequent increase in Ser136 phosphorylation (inactivation) of Bad, which is well known to promote apoptosis through the intrinsic mitochondrial pathway 43 .…”

Section: Discussionmentioning

confidence: 99%

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BET inhibitors synergize with sunitinib in melanoma through GDF15 suppression

Zeng

et al. 2023

Exp Mol Med

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Targeting bromodomain and extra-terminal domain (BET) proteins has shown a promising therapeutic effect on melanoma. The development of strategies to better kill melanoma cells with BET inhibitor treatment may provide new clinical applications. Here, we used a drug synergy screening approach to combine JQ1 with 240 antitumor drugs from the Food and Drug Administration (FDA)-approved drug library and found that sunitinib synergizes with BET inhibitors in melanoma cells. We further demonstrated that BET inhibitors synergize with sunitinib in melanoma by inducing apoptosis and cell cycle arrest. Mechanistically, BET inhibitors sensitize melanoma cells to sunitinib by inhibiting GDF15 expression. Strikingly, GDF15 is transcriptionally regulated directly by BRD4 or indirectly by the BRD4/IL6/STAT3 axis. Xenograft assays revealed that the combination of BET inhibitors with sunitinib causes melanoma suppression in vivo. Altogether, these findings suggest that BET inhibitor-mediated GDF15 inhibition plays a critical role in enhancing sunitinib sensitivity in melanoma, indicating that BET inhibitors synergize with sunitinib in melanoma.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

BET inhibitors synergize with sunitinib in melanoma through GDF15 suppression

Zeng

et al. 2023

Exp Mol Med

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“…The inactivation of phosphatase and tensin homolog (PTEN) leads to epithelial-mesenchymal transition and metastasis of NSCLC [42] and PTEN/PI3K/AKT signaling is implicated in the regulation of NSCLC tumorigenesis [43]. We herein identi ed PTEN as a direct target of miR-21-5p, and miR-21-5p inhibitor upregulated PTEN and inactivated PI3K/AKT signaling and reversed MEG3-knockdown induced PTEN downregulation and PI3K/AKT signaling activation in NSCLC cells.…”

Section: Discussionmentioning

confidence: 94%

HNRNPA2B1-mediated m6A modification of lncRNA MEG3 facilitates tumorigenesis and metastasis of non-small cell lung cancer by regulating miR-21-5p/PTEN axis

Li¹,

Gong²,

Xiang³

et al. 2023

Preprint

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Background Increasing data imply that heterogeneous nuclear ribonucleoprotein A2B1 (HNRNPA2B1) as a nuclear N6-methyladenosine (m6A) reader acts crucial roles in cancer progression. However, the role and underlying mechanism by which HNRNPA2B1-mediated m6A modification of lncRNA contributes to non-small cell lung cancer (NSCLC) remain undocumented. Methods The association of HNRNPA2B1 expression with the clinicopathological characteristics and prognosis in patients with NSCLC was determined by qRT-PCR, Western blot, immunohistochemistry and public datasets. The role of HNRNPA2B1 in NSCLC cells was assessed by the in vitro experiments and in vivo tumorigenesis and metastasis models. The m6A-lncRNA epi-transcriptomic microarray was employed to screen HNRNPA2B1-mediated m6A modification of lncRNAs, which were verified by methylated RNA immunoprecipitation (Me-RIP), RT-qPCR and rescue experiments in NSCLC cells. lncRNA MEG3-specific binding with miR-21-5p was validated by luciferase gene report and RIP assays. The effects of HNRNPA2B1 and (or) lncRNA MEG3 on miR-21-5p/PTEN/PI3K/AKT signaling were examined by RT-qPCR and Western blot analyses. Results We found that upregulation of HNRNPA2B1 was associated with distant metastasis and represented an independent prognostic factor for poor survival in patients with NSCLC. Knockdown of HNRNPA2B1 impaired cell proliferation and metastasis of NSCLC cells in vitro and in vivo, whereas ectopic expression of HNRNPA2B1 possessed the opposite effects. Mechanical investigations revealed that lncRNA MEG3 was identified as an m6A target of HNRNPA2B1 and inhibition of HNRNPA2B1 decreased the m6A level of lncRNA MEG3 but increased its expression levels. Furthermore, lncRNA MEG3 acted as a sponge of miR-21-5p, and knockdown of lncRNA MEG3 attenuated sh-HNRNPA2B1-caused inhibitory effects on cell colony formation and invasion. Elevated expression of miR-21-5p indicated poor survival in patients with NSCLC and inhibition of miR-21-5p counteracted si-MEG3-induced PTEN downregulation and PI3K/AKT signaling activation in NSCLC cells. Conclusions Our findings uncover that HNRNPA2B1-mediated m6A modification of lncRNA MEG3 promotes tumorigenesis and metastasis of NSCLC cells by regulating miR-21-5p/PTEN axis.

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“…GDF15 has been shown to regulate the PTEN/PI3K/AKT signaling pathway in different tumors 24 . In the present study, we demonstrated that knockdown of GDF15 remarkably inhibited the PTEN/PI3K/AKT signaling pathway and malignant melanoma.…”

Section: Discussionmentioning

confidence: 99%

Suppression of malignant melanoma by knocking down growth differentiation factor-15 via inhibiting PTEN/PI3K/AKT signaling pathway

Zhou,

Chen

2024

J. Cancer

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Background: Melanoma is a highly malignant tumor, and it is characterized by high mortality. Growth differentiation factor 15 (GDF15) and PTEN/PI3K/AKT signaling pathway have been proved to be related with regulation of tumors. If GDF15 could regulate melanoma through targeting PTEN/PI3K/AKT signaling pathway remain unclear. Methods: EdU staining, wound healing, Transwell assay, and flow cytometry were performed to measure cell proliferation, migration, invasion, and apoptosis. GEPIA and TCGA data bases were applied to analyze the relationship between GDF15 and prognosis. Results: We found that high expression of GDF15 suggested lower survival of melanoma patients, and is positively linked with advanced stage through analysis with GEPIA and TCGA data bases. Knockdown of GDF15 greatly inhibited the migration, invasion and proliferation ability of both M14 and M21 cells, but promoted cell apoptosis. However, the influence of GDF15 on M14 and M21 cells were reversed by 740Y-P, the activator of PTEN/PI3K/AKT signaling pathway. In addition, 740Y-P significantly reversed the influence of sh-GDF15 on the epithelial-mesenchymal transition (EMT) related proteins expression in M14 and M21 cell lines. Significant higher expression of GDF15 in melanoma was observed. In addition, the inhibition of PTEN/PI3K/AKT signaling pathway by knocking down GDF15 was observed in both M14 and M21 cell lines. sh-GDF15 greatly decreased the resistance of M14 and M21 to chemotherapy drugs, docetaxel and doxorubicin. Conclusions: GDF15 regulated the cell proliferation, apoptosis, migration, invasion, and EMT process of M14 and M21 cell lines through targeting PTEN/PI3K/AKT signaling pathway. This research provides a novel prevention and treatment strategy for melanoma.

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Knockdown of growth differentiation factor-15 inhibited nonsmall cell lung cancer through inactivating PTEN/PI3K/AKT signaling pathway

Cited by 6 publications

References 31 publications

BET inhibitors synergize with sunitinib in melanoma through GDF15 suppression

BET inhibitors synergize with sunitinib in melanoma through GDF15 suppression

HNRNPA2B1-mediated m6A modification of lncRNA MEG3 facilitates tumorigenesis and metastasis of non-small cell lung cancer by regulating miR-21-5p/PTEN axis

Suppression of malignant melanoma by knocking down growth differentiation factor-15 via inhibiting PTEN/PI3K/AKT signaling pathway

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