&lt;p&gt;TRIB3 suppresses proliferation and invasion and promotes apoptosis of endometrial cancer cells by regulating the AKT signaling pathway&lt;/p&gt;

Qu, Junjie; Liu, Binya; Li, Bilan; Du, Guiqiang; Li, Yiran; Wang, Jingyun; He, Laman; Wan, Xiaoping

doi:10.2147/ott.s189001

Cited by 25 publications

(18 citation statements)

References 38 publications

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“…Endometrial carcinoma is one of the most frequently diagnosed gynaecological malignancies, characterized by high rates of recurrence and poor prognosis. 22 Neddylation, a post-translational modification that conjugates the ubiquitin-like protein NEDD8 to substrate proteins, is an important biochemical process that regulates protein function. 20 The neddylation pathway is reported to be overactivated in multiple cancer types, including liver, lung and colon cancer, and its overactivation indicates poor prognosis.…”

Section: Discussionmentioning

confidence: 99%

MLN4924 inhibits cell proliferation by targeting the activated neddylation pathway in endometrial carcinoma

2021

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Objective To explore the neddylation pathway, found to be highly activated in various cancers, as a potential therapeutic target in endometrial carcinoma, one of the three most frequent malignant tumours in the female reproductive system. Methods Data from The Cancer Genome Atlas were analysed using online servers. Expression levels of key neddylation genes were validated by reverse-transcription polymerase chain reaction and western blots of tumour and adjacent tissues. Underlying mechanisms and the effects on cell activities of the neddylation pathway-specific inhibitor, MLN4924, were investigated in endometrial cancer cell lines. Results Key neddylation enzymes, ubiquitin conjugating enzyme E2 M ( UBC12), ubiquitin conjugating enzyme E2 F ( UBE2F), ring-box 1 ( RBX1) and ring finger protein 7 ( RBX2), were significantly overexpressed in endometrial carcinoma tissues versus normal tissues, but only UBE2F and RBX2 positively correlated with patient survival. MLN4924 significantly suppressed proliferation and colony formation in EC cells by inducing DNA re-replication, cell cycle arrest and apoptosis. Mechanism study revealed that MLN4924 induced the accumulation of cullin-RING ligase substrates in vitro. Conclusions The neddylation pathway was identified to play an important role in endometrial cancer. The neddylation specific inhibitor, MLN4924, may be a potential therapeutic drug for endometrial carcinoma.

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Section: Discussionmentioning

confidence: 99%

MLN4924 inhibits cell proliferation by targeting the activated neddylation pathway in endometrial carcinoma

2021

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“…Felip et al [ 12 ] found that ABTL0812 (an anti-cancer drug) inhibited the PI3K/AKT/mTORC1 axis by up-regulating the expression of TRIB3 to sensitize endometrial cancer cells. Qu et al [ 13 ] found that the expression level of TRIB3 in endometrial cancer cells was higher than that in normal endometrial tissue. The overexpression of TRIB3 promoted endometrial cell apoptosis, while it inhibited cell proliferation, migration and invasion.…”

Section: Introductionmentioning

confidence: 99%

Down-regulation of TRIB3 inhibits the progression of ovarian cancer via MEK/ERK signaling pathway

Wang

et al. 2020

Cancer Cell Int

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Background: Tribbles pseudokinase 3 (TRIB3) protein is a pseudokinase which plays an important role in cellular stress, metabolism, and tumor progression. However, the expression and function of TRIB3 in ovarian cancer is unknown. Methods: TRIB3 expression was detected by immunohistochemistry in the ovarian tissue samples. Following downregulation of TRIB3 by siRNA, multiple aspects of ovarian cancer cells were detected by the MTT assay, flow cytometry, scratch test and Transwell. Additionally, changes in related molecules and the MEK/ERK pathway were detected by western blotting. Finally, many bioinformatic methods, websites and databases, such as gene set enrichment analysis (GSEA), DVAID, Genemania, TISIDB and cBioPortal were used to study the TRIB3. Results: The expression level of TRIB3 was higher in ovarian epithelial malignant tumors as compared to other groups. Patients with a high expression level of TRIB3 had significantly shorter survival times,which was consistent with the results of analysis of the KM-plot database. Down-regulation of TRIB3 expression significantly inhibited the proliferation, invasion, and migration capabilities of ovarian cancer cells, and induced apoptosis and cell cycle arrest. Following TRIB3 siRNA transfection, expression levels of relative proteins were found to be decreased. Additionally, analysis in DAVID website and GSEA revealed that TRIB3 expression was associated with multiple biological processes. Protein phosphorylation levels of MEK and ERK also decreased following TRIB3-siRNA transfection. The Genemania website was used to analyze the proteins that interact with TRIB3. Analysis of TRIB3 in the TISIDB database and cBio-Portal website showed that ovarian cancer patients with high levels of mutation in TRIB3 had poor prognosis, and that the expression of TRIB3 was related to immunomodulation. Conclusions: The TRIB3 was highly expressed and promoting the malignant behavior of ovarian cancer cells by activating the MEK-ERK signaling pathway. It was also found to be associated with genetic variations and immune modulators.

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“…TRIB3 mediates differential regulation of the degree of Akt phosphorylation in different cells. In endometrial cancer cells, TRIB3 enhanced cell apoptosis and suppressed cell proliferation and migration ability through inhibition of Akt [14]. However, TRIB3 promoted oral squamous cell carcinoma cell proliferation by increasing Akt phosphorylation [31].…”

Section: Discussionmentioning

confidence: 97%

“…Yan reported that palmitic acid (PA), an important FFA constituent in GCs can induce endoplasmic reticulum stress (ERs) in a human hepatic cell line, accompanied by a signi cant induction of tribbles of pseudokinase 3 (TRIB3) expression, which was associated with decreased levels of phosphorylated Akt (p-Akt) [12]. Moreover, some other reports showed that TRIB3 induces abnormal Akt phosphorylation under high PA conditions in various cells [13][14][15]. On the other hand, TRIB3 was involved in cell proliferation and fatty acid oxidation signaling in bovine cumulus cells, which are also derived from follicular cells as granulosa cells and played a key role in oocyte meiotic resumption regulation [16].…”

Section: Introductionmentioning

confidence: 99%

TRIB3 Regulates FSHR Expression in Human Granulosa Cells Under High Levels of Free Fatty Acids

Wang

Lan

et al. 2021

Preprint

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Background: Granulosa cells (GCs) in cumulus oophorus highly express follicle stimulating hormone receptor (FSHR), which is the most important mediator of both estradiol synthesis and oocyte maturation. Obese women have elevated free fatty acids (FFAs) levels in their follicular fluids and decreased FSHR expression in GCs, which is related to an altered protein kinase B/glycogen synthase kinase 3β (Akt/GSK3β) signaling pathway. Such FFA increases accompany 3-fold rises in pseudokinase 3 (TRIB3) expression and reduce the Akt phosphorylation status in both the human liver and in insulinoma cell lines. Therefore, in a high FFA environment, we determined if TRIB3 mediates regulation of FSHR via the Akt/GSK3β signaling pathway in human GCs. Methods: GCs from women undergoing in vitro fertilization were collected and designated as high and low FFAs cohorts based on their follicular fluid FFA content. GCs with low FFA levels and a human granulosa-like tumor (KGN) cell line were exposed to palmitic acid (PA), which is a dominate FFA follicular fluid constituent. The effects were assessed of this substitution on the Akt/GSK3β signaling pathway activity as well as the expressions of TRIB3 and FSHR at both the gene and protein levels by qPCR, Western blot and immunofluorescence staining analyses. Meanwhile, the individual effects of TRIB3 knockdown in KGN cells and p-AKT inhibitors were compared to determine the mechanisms of FFA-induced FSHR downregulation.Results: The average FSH dose consuming per oocyte (FSH dose/oocyte) was elevated and Top embryo quality ratio was decreased in women with high levels of FFAs in their follicular fluid. In these women, the GC TRIB3 and ATF4 protein expression levels were upregulated which was accompanied by FSHR downregulation. Such upregulation was confirmed based on corresponding increases in their gene expression levels. On the other hand, the levels of p-Akt decreased while p-GSK3β increased in the GCs. Moreover, TRIB3 knockdown reversed declines in FSHR expression and estradiol (E2) production in KGN cells treated with PA, which also resulted in increased p-Akt levels and declines in the p-GSK3β level. In contrast, treatment of TRIB3-knockdown cells with an inhibitor of p-Akt (Ser473) resulted in rises in the levels of both p-GSK3β as well as FSHR expression whereas E2 synthesis fell. Conclusions: During exposure to a high FFA content, TRIB3 can reduce FSHR expression through stimulation of the Akt/GSK3β pathway in human GCs. This response may contribute to inducing oocyte maturation.

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<p>TRIB3 suppresses proliferation and invasion and promotes apoptosis of endometrial cancer cells by regulating the AKT signaling pathway</p>

Cited by 25 publications

References 38 publications

MLN4924 inhibits cell proliferation by targeting the activated neddylation pathway in endometrial carcinoma

MLN4924 inhibits cell proliferation by targeting the activated neddylation pathway in endometrial carcinoma

Down-regulation of TRIB3 inhibits the progression of ovarian cancer via MEK/ERK signaling pathway

TRIB3 Regulates FSHR Expression in Human Granulosa Cells Under High Levels of Free Fatty Acids

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