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Up-regulation of DRAM2 promotes tolerance of bladder transitional cell carcinoma to gemcitabine.

ABSTRACT: Introduction:Bladder transitional cell carcinoma (BTCC) is one of the most prevalent human malignant diseases. Gemcitabine is commonly applied in the treatment of BTCC while acquired gemcitabine resistance has caused a severe impediment to recovery. This study aimed to investigate the function of DRAM2 in regulating gemcitabine resistance of BTCC. Material and methods:GSE77883 was introduced to screen out the differentially expressed autophagy-related genes in T24 cells and gemcitabine-resistant T24-GEM cells. After establishing T24-GEM cells ourselves, aberrant expression of DRAM2 was detected by qRT-PCR and Western blot. After stably manipulating the expression of DRAM2 in T24 and T24-GEM cells, the changes of cell biological functions under gemcitabine treatment were compared, including cell viability, apoptosis and autophagy, using colony formation, flow cytometry and electron microscopy respectively. Results:DRAM2 was up-regulated in gemcitabine-resistant T24-GEM cells. Silencing of DRAM2 in T24-GEM cells inhibited the cell autophagy induced by treatment with gemcitabine and contributed to attenuated gemcitabine resistance. Also, overexpression of DRAM2 in T24 cells enhanced the autophagy, strengthened the chemoresistance and decreased the cell apoptosis rate under the treatment with gemcitabine. Conclusions:Our data suggested that downregulation of DRAM2 rescued the sensitivity of T24-GEM cells to gemcitabine, providing an appropriate therapeutic target for BTCC treatment.

SUBMITTER: Azhati B

PROVIDER: S-EPMC7444702 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Up-regulation of <i>DRAM2</i> promotes tolerance of bladder transitional cell carcinoma to gemcitabine.

Azhati Baihetiya B Maolakuerban Naibijiang N Ma Tao T Li Xiaodong X Rexiati Mulati M

Archives of medical science : AMS 20200527 5

<h4>Introduction</h4>Bladder transitional cell carcinoma (BTCC) is one of the most prevalent human malignant diseases. Gemcitabine is commonly applied in the treatment of BTCC while acquired gemcitabine resistance has caused a severe impediment to recovery. This study aimed to investigate the function of <i>DRAM2</i> in regulating gemcitabine resistance of BTCC.<h4>Material and methods</h4>GSE77883 was introduced to screen out the differentially expressed autophagy-related genes in T24 cells and ...[more]

PMID: 32864010

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Project description:Background:Bladder cancer (BC) is a common malignancy worldwide that accounts for 3% of global cancer diagnoses. Chemotherapy resistance limits the therapeutic effect of chemotherapeutic agents in patients with BC. Prolyl 4-hydroxylase, beta polypeptide (P4HB) is an endoplasmic reticulum (ER) chaperone that is upregulated in bladder cancer tissues (The Cancer Genome Atlas, TCGA datasets). Knockdown or suppression of P4HB exerts anticancer activity and sensitizes cells to chemotherapy in various types of cancer. Purpose:We aimed to investigate whether the inhibition of P4HB enhances the anticancer efficacy of gemcitabine (GEM) in BC cells and to study the underlying molecular mechanisms. Patients and Methods:The P4HB mRNA expression levels of 411 BC patients from the TCGA database and P4HB expression level of eighty BC paraffin-embedded samples detected by immunohistochemistry (IHC) staining were used for clinical feature and prognostic analyses. Bioinformatics analysis was utilized for the mechanistic investigation. Highly P4HB-expressed BC cell lines (T24 and 5637) treated with P4HB inhibitor (Bacitracin, BAC) were used to study the effects of BAC on the sensitivity of BC cells to GEM and the potential mechanism. P4HB inhibition experiments were performed in highly P4HB-expressed BC cells, and cell viability, colony formation, cell cycle, reactive oxygen species (ROS), apoptosis and pathway proteins were assessed in T24 and 5637 cells. Results:Western blot analysis showed that P4HB expression was significantly higher in BC tissues than in paired normal tissues. IHC showed that patients with high P4HB expression had a poorer overall survival (OS) rate than those with low P4HB expression. Furthermore, increased P4HB expression was demonstrated to be an independent prognostic marker for BC. Functionally, P4HB inhibition by BAC decreased the cell proliferation ability in vitro. Moreover, BAC treatment sensitized BC cells to GEM. Molecular mechanism analysis indicated that inhibition of P4HB by BAC treatment enhanced the anticancer effects of GEM through increasing cellular ROS content and promoting cell apoptosis and PERK/eIF2?/ATF4/CHOP signaling. Conclusion:High P4HB expression was significantly correlated with poor prognosis in BC patients. Inhibition of P4HB by BAC decreased the cell proliferation ability and sensitized BC cells to GEM by activating apoptosis and the PERK/eIF2?/ATF4/CHOP pathways.

Dataset Information

Up-regulation of DRAM2 promotes tolerance of bladder transitional cell carcinoma to gemcitabine.

Publications

Up-regulation of <i>DRAM2</i> promotes tolerance of bladder transitional cell carcinoma to gemcitabine.

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