MDM2 Increases Drug Resistance in Cancer Cells by Inducing EMT Independent of p53

Sun, Weichao; Tang, Liling

doi:10.2174/0929867323666160926150820

Cited by 18 publications

(12 citation statements)

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“…Increasing evidence suggests that the ATM pathway also plays essential roles in epithelial-mesenchymal transition (EMT), drug resistance, and cancer metastasis [ 15 16 17 18 19 20 21 22 23 24 ]. Sarris and colleagues [ 25 ] have reported that snail1 and other EMT markers are significantly upregulated in the livers or colons of wild-type mice after treatment with diethylnitrosamine or 1,2-dimethylhydrazine and dextran sodium sulfate.…”

Section: Discussionmentioning

confidence: 99%

ATM Signaling Pathway Is Implicated in the SMYD3-mediated Proliferation and Migration of Gastric Cancer Cells

Wang

Liu

et al. 2017

J Gastric Cancer

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PurposeWe previously found that the histone methyltransferase suppressor of variegation, enhancer of zeste, trithorax and myeloid-nervy-deformed epidermal autoregulatory factor-1 domain-containing protein 3 (SMYD3) is a potential independent predictive factor or prognostic factor for overall survival in gastric cancer patients, but its roles seem to differ from those in other cancers. Therefore, in this study, the detailed functions of SMYD3 in cell proliferation and migration in gastric cancer were examined.Materials and MethodsSMYD3 was overexpressed or suppressed by transfection with an expression plasmid or siRNA, and a wound healing migration assay and Transwell assay were performed to detect the migration and invasion ability of gastric cancer cells. Additionally, an MTT assay and clonogenic assay were performed to evaluate cell proliferation, and a cell cycle analysis was performed by propidium iodide staining. Furthermore, the expression of genes implicated in the ataxia telangiectasia mutated (ATM) pathway and proteins involved in cell cycle regulation were detected by polymerase chain reaction and western blot analyses.ResultsCompared with control cells, gastric cancer cells transfected with si-SMYD3 showed lower migration and invasion abilities (P<0.05), and the absence of SMYD3 halted cells in G2/M phase and activated the ATM pathway. Furthermore, the opposite patterns were observed when SMYD3 was elevated in normal gastric cells.ConclusionsTo the best of our knowledge, this study provides the first evidence that the absence of SMYD3 could inhibit the migration, invasion, and proliferation of gastric cancer cells and halt cells in G2/M phase via the ATM-CHK2/p53-Cdc25C pathway. These findings indicated that SMYD3 plays crucial roles in the proliferation, migration, and invasion of gastric cancer cells and may be a useful therapeutic target in human gastric carcinomas.

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Section: Discussionmentioning

confidence: 99%

ATM Signaling Pathway Is Implicated in the SMYD3-mediated Proliferation and Migration of Gastric Cancer Cells

Wang

Liu

et al. 2017

J Gastric Cancer

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“…The EMT occurs aberrantly during tumor progression and initiates the metastasis cascade and drug resistance ( 7 , 16 ). Here, we found that enforced expression of HOXB4 strongly suppressed the EMT process in breast cancer cells.…”

Section: Discussionmentioning

confidence: 99%

Homeobox B4 inhibits breast cancer cell migration by directly binding to StAR-related lipid transfer domain protein 13

et al. 2017

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The present study aimed to investigate the role of homeobox B4 (HOXB4) in breast cancer. Analysis of The Cancer Genome Atlas data revealed that HOXB4 expression was positively associated with expression of the StAR-related lipid transfer domain protein 13 (STARD13), and the overall survival of patients with breast cancer. Immunohistochemistry and quantitative polymerase chain reaction assays demonstrated that HOXB4 expression was downregulated in breast cancer tissues compared with adjacent normal tissues and was additionally positively associated with STARD13 expression. HOXB4 promoted STARD13 expression in breast cancer cells. Chromatin immunoprecipitation and luciferase reporter assays confirmed that HOXB4 directly bound to the STARD13 promoter. Additionally, HOXB4 inhibited breast cancer cell migration and the epithelial-mesenchymal transition through the STARD13/Ras homolog (Rho) family member A/Rho associated protein kinase signaling pathway. HOXB4 overexpression enhanced the sensitivity of breast cancer cells to doxorubicin and reversed resistance in doxorubicin-resistant cells. Overall, the results indicated that HOXB4 inhibited breast cancer cell migration and enhanced the sensitivity of breast cancer cells to doxorubicin by targeting STARD13.

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“…In addition to the classic MDM2–p53 loop dependent chemotherapeutic resistance in tumor cells, MDM2 can achieve chemotherapeutic resistance through a p53-independent pathway. MDM2 can increase chemotherapeutic resistance by inducing the epithelial mesenchymal transition (EMT) process [24], which is not only related to chemotherapeutic resistance but to target agents.…”

Section: Role Of Mdm2 and Therapeutic Resistancementioning

confidence: 99%

“…Stromal phenotypic tumor cells obtain stem cell-like characteristics and enhance their drug resistance through EMT [39]. MDM2 overexpression can promote EMT process in tumor cells to achieve chemotherapeutic drug resistance [24]. The EMT process is also associated with TKIs resistance in malignancies.…”

Section: Role Of Mdm2 and Therapeutic Resistancementioning

confidence: 99%

The role of MDM2 amplification and overexpression in therapeutic resistance of malignant tumors

2019

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The MDM2 protein encoded by the mouse double minute 2 ( MDM2 ) gene is the primary negative regulatory factor of the p53 protein. MDM2 can ligate the p53 protein via its E3 ubiquitin ligase, and the ubiquitinated p53 can be transferred to the cytoplasm and degraded by proteasomes. Therefore, MDM2 can maintain the stability of p53 signaling pathway. MDM2 amplification has been detected in many human malignancies, including lung cancer, colon cancer and other malignancies. MDM2 overexpression is associated with chemotherapeutic resistance in human malignancies. The mechanisms of chemotherapeutic resistance by MDM2 overexpression mainly include the p53–MDM2 loop-dependent and p53–MDM2 loop-independent pathways. But the role of MDM2 overexpression in tyrosine kinase inhibitors resistance remains to be further study. This paper reviews the possible mechanisms of therapeutic resistance of malignancies induced by MDM2 amplification and overexpression, including chemotherapy, radiotherapy, targeted agents and hyperprogressive disease of immunotherapy. Besides, MDM2-targeted therapy may be a potential new strategy for treating advanced malignancies.

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MDM2 Increases Drug Resistance in Cancer Cells by Inducing EMT Independent of p53

Cited by 18 publications

References 0 publications

ATM Signaling Pathway Is Implicated in the SMYD3-mediated Proliferation and Migration of Gastric Cancer Cells

ATM Signaling Pathway Is Implicated in the SMYD3-mediated Proliferation and Migration of Gastric Cancer Cells

Homeobox B4 inhibits breast cancer cell migration by directly binding to StAR-related lipid transfer domain protein 13

The role of MDM2 amplification and overexpression in therapeutic resistance of malignant tumors

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