Combination of phospholipase C[epsilon] knockdown with GANT61 sensitizes castration-resistant prostate cancer cells to enzalutamide by suppressing the androgen receptor signaling pathway
Castration-resistant prostate cancer (CRPC) is a major challenge in the treatment of prostate cancer (PCa). Phospholipase C[epsilon] (PLC[epsilon]), an oncogene, has been found to be involved in the carcinogenesis, tumor proliferation and migration of several types of cancer. The effects, however, o...
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| Veröffentlicht in: | Oncology reports 2019-05, Vol.41 (5), p.2689 |
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| creator | Sun, Wei Li, Luo Du, Zhongbo Quan, Zhen Yuan, Mengjuan Cheng, Honglin Gao, Yingying Luo, Chunli Wu, Xiaohou |
| description | Castration-resistant prostate cancer (CRPC) is a major challenge in the treatment of prostate cancer (PCa). Phospholipase C[epsilon] (PLC[epsilon]), an oncogene, has been found to be involved in the carcinogenesis, tumor proliferation and migration of several types of cancer. The effects, however, of PLC[epsilon] on CRPC remains unclear. In the present study, the expression of PLC[epsilon] and glioma-associated homolog (Gli)-1/Gli-2 in benign prostatic hyperplasia (BPH), PCa and CRPC tissues and cells was investigated, and the correlations between PLC[epsilon] and Gli-1/Gli-2 in CRPC tissues and cell lines were further explored. In addition, the effect of PLC[epsilon] on cell proliferation and invasion was assessed in CRPC cell lines, and the sensitivity of EN-R and 22RV1 cells to enzalutamide following the downregulation of PLC[epsilon] expression was determined using lentivirus-mediated shPLC[epsilon] and/or treatment with specific Gli inhibitor GANT61. It was found that the PLC[epsilon] expression was excessively upregulated in the majority of CRPC tissues, and PLC[epsilon] positivity was linked to poor progression-free survival (PFS) and overall survival (OS) in patients with PCa. Furthermore, PLC[epsilon] knockdown significantly suppressed CRPC cell proliferation and invasion. Of note, it was found that PLC[epsilon] knockdown increased the sensitivity of CRPC cells to enzalutamide in vitro by suppressing androgen receptor (AR) activities via the non-canonical Hedgehog/Gli-2 and p-STAT3 signaling pathways. PLC[epsilon] knockdown was shown to increase the sensitivity of CRPC cell xenografts to enzalutamide in vivo. Finally, the combination of PLC[epsilon] knockdown with GANT61 significantly sensitized CRPC cells to enzalutamide. Collectively, the results of the present study suggest that PLC[epsilon] is a potential therapeutic target for CRPC. |
| doi_str_mv | 10.3892/or.2019.7054 |
| format | Article |
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Phospholipase C[epsilon] (PLC[epsilon]), an oncogene, has been found to be involved in the carcinogenesis, tumor proliferation and migration of several types of cancer. The effects, however, of PLC[epsilon] on CRPC remains unclear. In the present study, the expression of PLC[epsilon] and glioma-associated homolog (Gli)-1/Gli-2 in benign prostatic hyperplasia (BPH), PCa and CRPC tissues and cells was investigated, and the correlations between PLC[epsilon] and Gli-1/Gli-2 in CRPC tissues and cell lines were further explored. In addition, the effect of PLC[epsilon] on cell proliferation and invasion was assessed in CRPC cell lines, and the sensitivity of EN-R and 22RV1 cells to enzalutamide following the downregulation of PLC[epsilon] expression was determined using lentivirus-mediated shPLC[epsilon] and/or treatment with specific Gli inhibitor GANT61. It was found that the PLC[epsilon] expression was excessively upregulated in the majority of CRPC tissues, and PLC[epsilon] positivity was linked to poor progression-free survival (PFS) and overall survival (OS) in patients with PCa. Furthermore, PLC[epsilon] knockdown significantly suppressed CRPC cell proliferation and invasion. Of note, it was found that PLC[epsilon] knockdown increased the sensitivity of CRPC cells to enzalutamide in vitro by suppressing androgen receptor (AR) activities via the non-canonical Hedgehog/Gli-2 and p-STAT3 signaling pathways. PLC[epsilon] knockdown was shown to increase the sensitivity of CRPC cell xenografts to enzalutamide in vivo. Finally, the combination of PLC[epsilon] knockdown with GANT61 significantly sensitized CRPC cells to enzalutamide. Collectively, the results of the present study suggest that PLC[epsilon] is a potential therapeutic target for CRPC.</description><identifier>ISSN: 1021-335X</identifier><identifier>DOI: 10.3892/or.2019.7054</identifier><language>eng</language><publisher>Spandidos Publications</publisher><subject>Androgen receptors ; Cancer cells ; Cancer treatment ; Carcinogenesis ; Care and treatment ; Cellular signal transduction ; Dosage and administration ; Enzalutamide ; Genetic aspects ; Gliomas ; Hyperplasia ; Phospholipases ; Prostate cancer ; Prostatic hyperplasia ; Tumors ; Vismodegib</subject><ispartof>Oncology reports, 2019-05, Vol.41 (5), p.2689</ispartof><rights>COPYRIGHT 2019 Spandidos Publications</rights><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids></links><search><creatorcontrib>Sun, Wei</creatorcontrib><creatorcontrib>Li, Luo</creatorcontrib><creatorcontrib>Du, Zhongbo</creatorcontrib><creatorcontrib>Quan, Zhen</creatorcontrib><creatorcontrib>Yuan, Mengjuan</creatorcontrib><creatorcontrib>Cheng, Honglin</creatorcontrib><creatorcontrib>Gao, Yingying</creatorcontrib><creatorcontrib>Luo, Chunli</creatorcontrib><creatorcontrib>Wu, Xiaohou</creatorcontrib><title>Combination of phospholipase C[epsilon] knockdown with GANT61 sensitizes castration-resistant prostate cancer cells to enzalutamide by suppressing the androgen receptor signaling pathway</title><title>Oncology reports</title><description>Castration-resistant prostate cancer (CRPC) is a major challenge in the treatment of prostate cancer (PCa). Phospholipase C[epsilon] (PLC[epsilon]), an oncogene, has been found to be involved in the carcinogenesis, tumor proliferation and migration of several types of cancer. The effects, however, of PLC[epsilon] on CRPC remains unclear. In the present study, the expression of PLC[epsilon] and glioma-associated homolog (Gli)-1/Gli-2 in benign prostatic hyperplasia (BPH), PCa and CRPC tissues and cells was investigated, and the correlations between PLC[epsilon] and Gli-1/Gli-2 in CRPC tissues and cell lines were further explored. In addition, the effect of PLC[epsilon] on cell proliferation and invasion was assessed in CRPC cell lines, and the sensitivity of EN-R and 22RV1 cells to enzalutamide following the downregulation of PLC[epsilon] expression was determined using lentivirus-mediated shPLC[epsilon] and/or treatment with specific Gli inhibitor GANT61. It was found that the PLC[epsilon] expression was excessively upregulated in the majority of CRPC tissues, and PLC[epsilon] positivity was linked to poor progression-free survival (PFS) and overall survival (OS) in patients with PCa. Furthermore, PLC[epsilon] knockdown significantly suppressed CRPC cell proliferation and invasion. Of note, it was found that PLC[epsilon] knockdown increased the sensitivity of CRPC cells to enzalutamide in vitro by suppressing androgen receptor (AR) activities via the non-canonical Hedgehog/Gli-2 and p-STAT3 signaling pathways. PLC[epsilon] knockdown was shown to increase the sensitivity of CRPC cell xenografts to enzalutamide in vivo. Finally, the combination of PLC[epsilon] knockdown with GANT61 significantly sensitized CRPC cells to enzalutamide. Collectively, the results of the present study suggest that PLC[epsilon] is a potential therapeutic target for CRPC.</description><subject>Androgen receptors</subject><subject>Cancer cells</subject><subject>Cancer treatment</subject><subject>Carcinogenesis</subject><subject>Care and treatment</subject><subject>Cellular signal transduction</subject><subject>Dosage and administration</subject><subject>Enzalutamide</subject><subject>Genetic aspects</subject><subject>Gliomas</subject><subject>Hyperplasia</subject><subject>Phospholipases</subject><subject>Prostate cancer</subject><subject>Prostatic hyperplasia</subject><subject>Tumors</subject><subject>Vismodegib</subject><issn>1021-335X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><sourceid/><recordid>eNptUM1KJDEQ7sMu6Ko3H6BgYW89Jt2T_jkOg6uCuJc5LCwilUylO2smaboigz7aPp3R9aAgRVEf309BVVGcSrGou746i_OiErJftEItvxSHUlSyrGv1-6D4xvxXiKoVTX9Y_FvHnXYBk4sBooVpjJzbuwmZYP2HJnY-hlu4D9Hcb-M-wN6lES5WN5tGAlNgl9wTMRjkNL_uKWdixwlDgmmOGSTKajA0gyHvGVIECk_oHxLu3JZAPwI_TFOOsQsDpJEAw3aOAwWYydCU4gzshoD-RZ8wjXt8PC6-WvRMJ2_zqNj8PN-sL8vrXxdX69V1OfRdV7aNFgqXQhkrhDS6saitRpsx9lLWyrZV1y3bpbSEGhshJWaSGqE09rqrj4rv_9cO6OnOBRvzmWbn2NytVFc3vVLixbX4xJVrSztnYiDrMv8h8ONdYCT0aeSYX5IfyO-Nz5CJlOk</recordid><startdate>20190501</startdate><enddate>20190501</enddate><creator>Sun, Wei</creator><creator>Li, Luo</creator><creator>Du, Zhongbo</creator><creator>Quan, Zhen</creator><creator>Yuan, Mengjuan</creator><creator>Cheng, Honglin</creator><creator>Gao, Yingying</creator><creator>Luo, Chunli</creator><creator>Wu, Xiaohou</creator><general>Spandidos Publications</general><scope/></search><sort><creationdate>20190501</creationdate><title>Combination of phospholipase C[epsilon] knockdown with GANT61 sensitizes castration-resistant prostate cancer cells to enzalutamide by suppressing the androgen receptor signaling pathway</title><author>Sun, Wei ; Li, Luo ; Du, Zhongbo ; Quan, Zhen ; Yuan, Mengjuan ; Cheng, Honglin ; Gao, Yingying ; Luo, Chunli ; Wu, Xiaohou</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-g988-76b05a405cf001cb6fabfbaf01ca91135f72884741feaba6011a35fe605ba9b83</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>Androgen receptors</topic><topic>Cancer cells</topic><topic>Cancer treatment</topic><topic>Carcinogenesis</topic><topic>Care and treatment</topic><topic>Cellular signal transduction</topic><topic>Dosage and administration</topic><topic>Enzalutamide</topic><topic>Genetic aspects</topic><topic>Gliomas</topic><topic>Hyperplasia</topic><topic>Phospholipases</topic><topic>Prostate cancer</topic><topic>Prostatic hyperplasia</topic><topic>Tumors</topic><topic>Vismodegib</topic><toplevel>online_resources</toplevel><creatorcontrib>Sun, Wei</creatorcontrib><creatorcontrib>Li, Luo</creatorcontrib><creatorcontrib>Du, Zhongbo</creatorcontrib><creatorcontrib>Quan, Zhen</creatorcontrib><creatorcontrib>Yuan, Mengjuan</creatorcontrib><creatorcontrib>Cheng, Honglin</creatorcontrib><creatorcontrib>Gao, Yingying</creatorcontrib><creatorcontrib>Luo, Chunli</creatorcontrib><creatorcontrib>Wu, Xiaohou</creatorcontrib><jtitle>Oncology reports</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Sun, Wei</au><au>Li, Luo</au><au>Du, Zhongbo</au><au>Quan, Zhen</au><au>Yuan, Mengjuan</au><au>Cheng, Honglin</au><au>Gao, Yingying</au><au>Luo, Chunli</au><au>Wu, Xiaohou</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Combination of phospholipase C[epsilon] knockdown with GANT61 sensitizes castration-resistant prostate cancer cells to enzalutamide by suppressing the androgen receptor signaling pathway</atitle><jtitle>Oncology reports</jtitle><date>2019-05-01</date><risdate>2019</risdate><volume>41</volume><issue>5</issue><spage>2689</spage><pages>2689-</pages><issn>1021-335X</issn><abstract>Castration-resistant prostate cancer (CRPC) is a major challenge in the treatment of prostate cancer (PCa). Phospholipase C[epsilon] (PLC[epsilon]), an oncogene, has been found to be involved in the carcinogenesis, tumor proliferation and migration of several types of cancer. The effects, however, of PLC[epsilon] on CRPC remains unclear. In the present study, the expression of PLC[epsilon] and glioma-associated homolog (Gli)-1/Gli-2 in benign prostatic hyperplasia (BPH), PCa and CRPC tissues and cells was investigated, and the correlations between PLC[epsilon] and Gli-1/Gli-2 in CRPC tissues and cell lines were further explored. In addition, the effect of PLC[epsilon] on cell proliferation and invasion was assessed in CRPC cell lines, and the sensitivity of EN-R and 22RV1 cells to enzalutamide following the downregulation of PLC[epsilon] expression was determined using lentivirus-mediated shPLC[epsilon] and/or treatment with specific Gli inhibitor GANT61. It was found that the PLC[epsilon] expression was excessively upregulated in the majority of CRPC tissues, and PLC[epsilon] positivity was linked to poor progression-free survival (PFS) and overall survival (OS) in patients with PCa. Furthermore, PLC[epsilon] knockdown significantly suppressed CRPC cell proliferation and invasion. Of note, it was found that PLC[epsilon] knockdown increased the sensitivity of CRPC cells to enzalutamide in vitro by suppressing androgen receptor (AR) activities via the non-canonical Hedgehog/Gli-2 and p-STAT3 signaling pathways. PLC[epsilon] knockdown was shown to increase the sensitivity of CRPC cell xenografts to enzalutamide in vivo. Finally, the combination of PLC[epsilon] knockdown with GANT61 significantly sensitized CRPC cells to enzalutamide. Collectively, the results of the present study suggest that PLC[epsilon] is a potential therapeutic target for CRPC.</abstract><pub>Spandidos Publications</pub><doi>10.3892/or.2019.7054</doi></addata></record> |
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| subjects | Androgen receptors Cancer cells Cancer treatment Carcinogenesis Care and treatment Cellular signal transduction Dosage and administration Enzalutamide Genetic aspects Gliomas Hyperplasia Phospholipases Prostate cancer Prostatic hyperplasia Tumors Vismodegib |
| title | Combination of phospholipase C[epsilon] knockdown with GANT61 sensitizes castration-resistant prostate cancer cells to enzalutamide by suppressing the androgen receptor signaling pathway |
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