Silencing of B7-H3 increases gemcitabine sensitivity by promoting apoptosis in pancreatic carcinoma

Zhao, Xin; Zhang, Guangbo; Gan, Wen-Juan; Xiong, Feng; Li, Zhi; Zhao, Hua; Zhu, Dongming; Zhang, Bin; Zhang, Xueguang; Li, Dechun

doi:10.3892/ol.2013.1118

Cited by 49 publications

(48 citation statements)

References 24 publications

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“…Our findings in vivo demonstrated that the B7-H3 silence apparently enhanced the chemosensitivity of rituximab and bendamustine to mantle cell lymphoma in the xenograft model. Similar promoting effects of B7-H3 on cancer resistance to drug treatments in breast cancer (26) and pancreatic carcinoma (27) xenograft models have been reported.…”

Section: Discussionmentioning

confidence: 51%

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B7-H3 silencing inhibits tumor progression of mantle cell lymphoma and enhances chemosensitivity

Zhang

Wang

et al. 2015

International Journal of Oncology

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Abstract. B7-H3 (CD276), known as a member of B7 immunoregulatory family, is a type I transmembrane glycoprotein aberrantly expressed in numerous types of cancer and associated with poor prognosis. However, the role of B7-H3 in oncogenesis and chemosensitivity of mantle cell lymphoma (MCL) remains unknown. We determined the effects of downregulating B7-H3 expression on tumor progression and the sensitivity of chemotherapeutic drug in mantle cell lymphoma. B7-H3 knockdown was performed using lentivirus transduction in the Maver and Z138 mantle cell lymphoma cell lines, respectively. The effects of B7-H3 on cell proliferation, cycle, migration and invasion were investigated by CCK-8 assay, methyl cellulose colony forming assay, PI staining, and Transwell assays in vitro. By establishing Maver and Z138 xenograft models, the effects of B7-H3 on tumorigenicity were observed, and Ki-67 and PCNA was detected by immunohistochemistry. The downregulation of B7-H3 significantly decreased tumor proliferation in MCL in vitro and in vivo. In the B7-H3 knockdown groups of Maver and Z138 xenograft models, the mean inhibition rate of tumor growth was 59.1 and 65.0% (p=0.010 and 0.003), and the expression of both Ki-67 and PCNA were significantly lower, respectively. After B7-H3 silencing, the cell cycles of Maver and Z138 were both arrested at G0/G1 phase, and the cell migration rates and invasion capacity were decreased as well. Moreover, the impacts of B7-H3 RNAi on the antitumor effect of chemotherapy drugs were determined with CCK-8 and Annexin V-FITC/PI assays in vitro and with xenograft models in vivo. The silencing of B7-H3 increased the sensitivity of Maver and Z138 cells to rituximab and bendamustine and enhanced the drug-induced apoptosis, respectively. Our study demonstrates for the first time that B7-H3 promotes mantle cell lymphoma progression and B7-H3 knockdown significantly enhances the chemosensitivity. This may provide a new therapeutic approach to mantle cell lymphoma. IntroductionMantle cell lymphoma (MCL), a heterogeneous subtype of B-cell non-Hodgkin lymphoma (NHL), accounts for ~7% of NHL cases in the USA and Europe and has one of the worst outcomes of all the lymphomas (1,2). It is characterized by the t(11;14) (q13;q32) translocation, which results in overexpression of cyclin D1 and deregulation of the cell cycle (2). At initial diagnosis, most patients with the median age ~68-70 years have advanced stage disease, and the median overall survival is 3-5 years (3). Although several novel agents have proven to be effective, MCL remains a largely incurable disease and the following relapse is still challenging. Therefore, understanding the molecular mechanisms of MCL pathogenesis and drug resistance will aid in the development of highly active targeted therapies for the disease.B7-H3, a new member of B7 immunoregulatory family with immunoglobulin-like structure (4), is induced in activated dendritic cells, monocytes and T cells (5). Aberrant expression of B7-H3 has been reported and associated with poor prog...

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Section: Discussionmentioning

confidence: 51%

“…Liu et al discovered that silencing of B7-H3 sensitized the breast cancer cell lines to paclitaxel by abrogating Jak2/Stat3 phosphorylation (26). In pancreatic carcinoma cells, B7-H3 was demonstrated to induce gemcitabine resistance as well (27). The above research indicated that B7-H3 may be a potential therapeutic target.…”

Section: Introductionmentioning

confidence: 84%

B7-H3 silencing inhibits tumor progression of mantle cell lymphoma and enhances chemosensitivity

Zhang

Wang

et al. 2015

International Journal of Oncology

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“…Furthermore, it is reported that inhibition of B7-H3 by siRNA significantly suppresses cell migration and invasion, enhances sensitivity to chemotherapeutic drugs in acute monocytic leukemia U937 cells [30]. In pancreatic carcinoma, it is suggested that silencing of B7-H3 increases gemcitabine sensitivity through induction of surviving-dependent apoptosis [31]. In our study, the mRNA and protein levels of B7-H3 were remarkably reduced in NSCLC cells treated with cisplatin and astragaloside IV, suggesting that astragaloside IV increased cisplatin sensitivity via downregulating B7-H3 expression.…”

Section: Discussionmentioning

confidence: 99%

Astragaloside IV Enhances Cisplatin Chemosensitivity in Non-Small Cell Lung Cancer Cells Through Inhibition of B7-H3

Liu

et al. 2016

Cell Physiol Biochem

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Background: Chemoresistance is a major obstacle to successful chemotherapy for human non-small cell lung cancer (NSCLC). Astragaloside IV, the component of Astragalus membranaceus, has been reported to exhibit anti-inflammation, anti-cancer and immunoregulatory properties. In the present study, we investigated the role of astragaloside IV in the chemoresistance to cisplatin in NSCLC cells. Methods: We established astragaloside IV-suppressed NSCLC cell lines including A549, HCC827, and NCI-H1299 and evaluated their sensitivity to cisplatin in vitro. In addition, we examined the mRNA and protein levels of B7-H3 in response to cisplatin-based chemotherapy. Results: We showed that high doses of astragaloside IV (10, 20, 40 ng/ml) inhibited NSCLC cell growth, whereas low concentrations of astragaloside IV (1, 2.5, 5 ng/ml) had no obvious cytotoxicity on cell viability. Moreover, combined treatment with astragaloside IV significantly increased chemosensitivity to cisplatin in NSCLC cells. On the molecular level, astragaloside IV co-treatment significantly inhibited the mRNA and protein levels of B7-H3 in the presence of cisplatin. In addition, ectopic expression of B7-H3 diminished the sensitization role of astragaloside IV in cellular responses to cisplatin in NSCLC cells. Conclusion: These results demonstrate that astragaloside IV enhances chemosensitivity to cisplatin via inhibition of B7-H3 and that treatment with astragaloside IV and inhibition of B7-H3 serve as potential therapeutic approach for lung cancer patients.

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“…We and others have shown that B7-H3 mediates breast cancer invasion, metastasis and drug resistance and that silencing B7-H3 delays tumor growth and sensitizes cancer cells to chemotherapeutic agents (16–21). Similar results have also been confirmed by other groups in pancreatic cancer (21,22), colorectal cancer (20), hepatocellular carcinoma (23) and melanoma (19,24). In addition, we and others have shown that B7-H3 overexpression in breast cancer, melanoma and osteosarcoma cells increases their metastatic potential (16,19,25).…”

Section: Introductionmentioning

confidence: 99%

Immunoregulatory Protein B7-H3 Reprograms Glucose Metabolism in Cancer Cells by ROS-Mediated Stabilization of HIF1α

et al. 2016

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B7-H3 is a member of B7 family of immunoregulatory transmembrane glycoproteins expressed by T cells. While B7-H3 overexpression is associated with poor outcomes in multiple cancers, it is also has immune-independent roles outside T cells and its precise mechanistic contributions to cancer are unclear. In this study, we investigated the role of B7-H3 in metabolic reprogramming of cancer cells in vitro and in vivo. We found that B7-H3 promoted the Warburg effect, evidenced by increased glucose uptake and lactate production in B7-H3-expressing cells. B7-H3 also increased the protein levels of HIF-1α and its downstream targets, LDHA and PDK1, key enzymes in the glycolytic pathway. Further, B7-H3 promoted ROS-dependent stabilization of HIF-1α by suppressing the activity of the stress-activated transcription factor Nrf2 and its target genes, including the antioxidants SOD1, SOD2, and PRX3. Metabolic imaging of human breast cancer xenografts in mice confirmed that B7-H3 enhanced tumor glucose uptake and tumor growth. Together, our results illuminate the critical immune-independent contributions of B7-H3 to cancer metabolism, presenting a radically new perspective on B7 family immunoregulatory proteins in malignant progression.

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Silencing of B7-H3 increases gemcitabine sensitivity by promoting apoptosis in pancreatic carcinoma

Cited by 49 publications

References 24 publications

B7-H3 silencing inhibits tumor progression of mantle cell lymphoma and enhances chemosensitivity

B7-H3 silencing inhibits tumor progression of mantle cell lymphoma and enhances chemosensitivity

Astragaloside IV Enhances Cisplatin Chemosensitivity in Non-Small Cell Lung Cancer Cells Through Inhibition of B7-H3

Immunoregulatory Protein B7-H3 Reprograms Glucose Metabolism in Cancer Cells by ROS-Mediated Stabilization of HIF1α

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