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ATF6? Activation Enhances Survival against Chemotherapy and Serves as a Prognostic Indicator in Osteosarcoma.

ABSTRACT: Patients with metastatic or relapsed/refractory osteosarcoma (OS) have a 5-year survival rate of <30%. This has remained unchanged over several decades. One of the factors contributing to lack of improvement in survival is the development of chemoresistance. Hence, elucidating and targeting the mechanisms that promote survival against chemotherapy and lead to chemoresistance is pivotal to improving outcomes for these patients. We identified that endoplasmic reticulum (ER) stress-activated transcription factor, ATF6?, is essential for the survival of OS cells against chemotherapy induced cell death. ATF6? cleavage and activity were enhanced in OS cells compared to normal osteoblasts and knockdown of ATF6? expression enhanced sensitivity of OS cells against chemotherapy induced cell death. This was in part due to increased Bax activation. Pharmacologic inhibition or knock-down of downstream targets of ATF6?, protein disulfide isomerases (PDI) and ERO1?, a thiol oxidase that is involved in the re-oxidation of PDIs also independently induced pronounced killing of OS cells following chemotherapy. Analysis of primary tumors from OS patients reveals that patients with high levels of nuclear ATF6?: (1) also had increased expression of its downstream targets the chaperone BiP and enzyme PDI, (2) had a significant likelihood of developing metastasis at diagnosis, (3) had significantly poorer overall and progression free survival, and (4) had poorer response to chemotherapy. These findings suggest that targeting survival signaling by the ATF6? pathway in OS cells may favor eradication of refractory OS tumor cells and ATF6? could be a useful predictor for chemo-responsiveness and prognosis.

SUBMITTER: Yarapureddy S

PROVIDER: S-EPMC6484364 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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ATF6α Activation Enhances Survival against Chemotherapy and Serves as a Prognostic Indicator in Osteosarcoma.

Yarapureddy Suma S Abril Jazmine J Foote Janet J Kumar Saravana S Asad Omar O Sharath Veena V Faraj Janine J Daniel Dustin D Dickman Paul P White-Collins Andrea A Hingorani Pooja P Sertil Aparna R AR

Neoplasia (New York, N.Y.) 20190425 6

Patients with metastatic or relapsed/refractory osteosarcoma (OS) have a 5-year survival rate of <30%. This has remained unchanged over several decades. One of the factors contributing to lack of improvement in survival is the development of chemoresistance. Hence, elucidating and targeting the mechanisms that promote survival against chemotherapy and lead to chemoresistance is pivotal to improving outcomes for these patients. We identified that endoplasmic reticulum (ER) stress-activated transc ...[more]

PMID: 31029032

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Project description:Background: Hepatocellular carcinoma (HCC) is a tumor with high malignancy and poor 5-years survival rate. Excellent tumor markers are very important for early clinical diagnosis and prognosis evaluation. Previous studies have shown that CDK2AP1 (Cyclin-dependent kinase 2-associated protein 1) is involved in cell-cycle and epigenetic regulation. In the present study, we assess CDK2AP1 expression, prognostic value, immunomodulatory and possible influencing pathways in HCC. Method: The Cancer Genome Atlas (TCGA) database was used to analyse gene expression, clinicopathology and prognosis. The protein level of CDK2AP1 in HCC tissues was detected in the Human Protein Atlas (HPA) database. The immune score in HCC to CDKAP1 expression were analyzed using ESTIMATE. Furthermore, we use Tumor IMmune Estimation Resource (TIMER) database to study CDK2AP1 expression and Immune Infiltration Levels in HCC. Co-expressed genes of CDK2AP1 were predicted and elaborated by LinkedOmics. Results: In normal liver tissues, the expression of CDK2AP1 was significantly lower than tumor tissues, and was correlated with the level of clinical stage and histologic grade in HCC patients. Patients with high expression of CDK2AP1 have a poor prognosis than patients with low CDK2AP1 expression. CDK2AP1 expression level exhibits significantly positive correlations with the number of infiltrating B cells, CD4+ T cells, CD8+ T cells, Macrophages, Neutrophils, and DCs in HCC tissues. KEGG enrichment analysis showed that the related pathways affected by CDK2AP1 mainly include: Fc gamma R-mediated phagocytosis, Th1 and Th2 cell differentiation, Cell cycle, etc. Both in vitro and in vivo experiments confirmed that CDK2AP1 promotes the proliferation and metastasis in hepatocellular carcinoma. Our results highlight the role of CDK2AP1 as an important prognostic indicator and immunotherapy target for HCC patients. Conclusion: We found CDK2AP1 as a new prognostic biomarker for HCC, which could help explain changes in the biological processes and immune environment lead to liver cancer development. Therefore, CDK2AP1 is a potential new target for HCC therapy.

Project description:Background and objectiveLiver cancer is a malignancy with a poor prognosis. G protein signaling modulator 2 is mainly related to cell division and cell cycle regulation. In this review, the relationship between G protein signaling modulator 2 and clinical characteristics of patients with liver cancer has been explored, especially with respect to its prognostic value.MethodsG protein signaling modulator 2 messenger RNA expression and clinicopathological characteristics of patients with liver cancer were obtained from The Cancer Genome Atlas. The expression level of G protein signaling modulator 2 RNA-Seq was validated by using Gene Expression Omnibus. Chi-square test was performed to evaluate the relationship between G protein signaling modulator 2 expression and clinical characteristics. The threshold value of G protein signaling modulator 2 in the diagnosis of liver cancer was evaluated by a receiver-operating characteristic curve. Cox regression analysis and Kaplan-Meier curves were performed to evaluate the relationship between G protein signaling modulator 2 and liver cancer prognosis, which included overall and residual-free survival, and explored the prognostic value of G protein signaling modulator 2. Liver cancer survival analyses were validated by using the data of G protein signaling modulator 2 RNA-Seq from the International Cancer Genome Consortium.ResultsThe expression level of G protein signaling modulator 2 messenger RNA was remarkably higher in liver cancer than that in healthy tissues (P < 2.2 × e-16), which was also validated by data from the GSE14520 database. In addition, high G protein signaling modulator 2 expression significantly correlated with histological grade (P = .020), vital status (P < .001), clinical (P = .001), and T stage (P = .001). The receiver-operating characteristic curves showed G protein signaling modulator 2 to be an advantageous diagnostic molecule for liver cancer (area under curve = 0.893). Furthermore, the results of Cox analysis and Kaplan-Meier curves suggested that the upregulation of G protein signaling modulator 2 expression is linked to poor prognosis and G protein signaling modulator 2 messenger RNA could be an independent predictor for liver cancer, which was validated by data from the International Cancer Genome Consortium database.ConclusionsG protein signaling modulator 2 messenger RNA was overexpressed in liver cancer, and G protein signaling modulator 2 is an independent prognostic factor. G protein signaling modulator 2 is expected to be a treatment target for cancer.

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Dataset Information

ATF6? Activation Enhances Survival against Chemotherapy and Serves as a Prognostic Indicator in Osteosarcoma.

Publications

ATF6α Activation Enhances Survival against Chemotherapy and Serves as a Prognostic Indicator in Osteosarcoma.

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