Dataset Information

PPAR? activation serves as therapeutic strategy against bladder cancer via inhibiting PI3K-Akt signaling pathway.

ABSTRACT:

Background

Heterogeneity in bladder cancer results in variable clinical outcomes, posing challenges for clinical management of this malignancy. Recent studies suggest both tumor suppressive and oncogenic role of PPAR? in bladder cancer. The fuction of PPAR? signaling pathway in modulating carcinogenesis is controversial.

Methods

The expression of PPAR? and association with overall survival were analyzed in patients from two cohorts. The effect of PPAR? activation on cell proliferation, cell cycle, and cell apoptosis were determined with the agonists (rosiglitazone and pioglitazone), the inverse agonist (T0070907), and the antagonist (GW9662) in Umuc-3 and 5637 bladder cancer cells. The correlation of PPAR? activation with PI3K-Akt pathway was evaluated with RNA sequencing data from the TCGA cases and 30 human bladder cancer cell lines. The effect of PPAR? activation on tumor growth was validated with subcutaneous tumor models in vivo. The effect of PPAR? activation on PI3K-Akt signaling transduction was determined with multiple assays including immunohistochemistry, flow cytometry, proteomic array, and western blotting.

Results

We showed that PPAR? was a favorable prognostic factor in patients with bladder cancer. PPAR? activation by rosiglitazone and pioglitazone markedly induced cell cycle G2 arrest and apoptosis in bladder cancer cells, which resulted in inhibition of cell proliferation in vitro and suppression of tumor growth in vivo. The underlying mechanism involved marked inhibition of PI3K-Akt pathway.

Conclusions

This study reported the tumor-suppressive effect of PPAR? agonists in bladder cancer, suggesting that transactivation of PPAR? could be served as a potential strategy for the chemoprevention and therapeutic treatment of bladder cancer.

SUBMITTER: Lv S

PROVIDER: S-EPMC6407222 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Publications

PPARγ activation serves as therapeutic strategy against bladder cancer via inhibiting PI3K-Akt signaling pathway.

Lv Shidong S Wang Wei W Wang Hongyi H Zhu Yongtong Y Lei Chengyong C

BMC cancer 20190307 1

<h4>Background</h4>Heterogeneity in bladder cancer results in variable clinical outcomes, posing challenges for clinical management of this malignancy. Recent studies suggest both tumor suppressive and oncogenic role of PPARγ in bladder cancer. The fuction of PPARγ signaling pathway in modulating carcinogenesis is controversial.<h4>Methods</h4>The expression of PPARγ and association with overall survival were analyzed in patients from two cohorts. The effect of PPARγ activation on cell prolifera ...[more]

PMID: 30845932

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Project description:Methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) has been implicated in the etiology of various human malignant tumors; however, its exact role in bladder cancer (BC) remains to be explored. Through reverse transcription‑quantitative PCR, western blotting and immunohistochemistry detection of BC tissue, combined with The Cancer Genome Atlas (TCGA) database analysis, the present study demonstrated that MTHFD2 was upregulated in BC tissues. MTHFD2 expression in patients with BC was frequently associated with worse prognosis, tumor immune cell infiltration and programmed death‑ligand 1 (PD‑L1) expression. Subsequently, using short hairpin RNA, the expression levels of MTHFD2 were knocked down in BC cell lines, and the results revealed that the tumor cell proliferation and colony formation abilities of cells were greatly reduced, as determined by Cell Counting Kit 8 and colony formation assays, as was the expression of PD‑L1, as determined by western blotting. These findings were also confirmed in a xenograft nude mouse model. Simultaneously, it was revealed that abnormal expression of MTHFD2 was closely associated with the PI3K/AKT signaling pathway in both RNA‑sequencing and TCGA datasets. This observation was verified in vitro by detecting the protein expression levels of PI3K and AKT by western blotting. The activation of PI3K and AKT was enhanced in BC cells (T24) following stimulation with 740Y‑P, a PI3K activator, and cellular activities and PD‑L1 expression levels were restored. Finally, it was demonstrated that the MTHFD2 levels were correlated with chemosensitivity to traditional BC chemotherapeutic agents and various PI3K/AKT‑targeted drugs, as determined by analyzing the Genomics of Drug Sensitivity in Cancer database. Overall, the present findings revealed that upregulation of MTHFD2 was associated with PD‑L1 activation in BC via the PI3K/AKT signaling pathway, suggesting that it could be a promising marker of chemotherapy and immunotherapy for BC.