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Ref Type | Journal Article |
PMID | (23463670) |
Authors | Sun NK, Huang SL, Chang TC, Chao CC |
Title | Sorafenib induces endometrial carcinoma apoptosis by inhibiting Elk-1-dependent Mcl-1 transcription and inducing Akt/GSK3β-dependent protein degradation. |
Journal | Journal of cellular biochemistry |
Vol | 114 |
Issue | 8 |
Date | 2013 Aug |
URL | |
Abstract Text | Endometrial carcinoma (EC) is one of the main gynecologic malignancies affecting women, but effective treatments are currently lacking. In the present study, we investigated the effect of sorafenib, a general kinase inhibitor, on several EC cell lines (HEC1A, HEC1B, and RL95-2). Sorafenib induced cell death in EC cells with the following order of sensitivity: HEC1A > HEC1B > RL95-2. Sorafenib suppressed several anti-apoptotic proteins in HEC1A cells, including myeloid cell leukemia 1 (Mcl-1). Ectopic overexpression of Mcl-1 prevented the cell killing effect of sorafenib. Sorafenib suppressed Mcl-1 at the gene transactivation level by inactivating the ERK/Elk-1 pathway. Accordingly, the inhibitory effect of sorafenib on Mcl-1 expression decreased following knockdown of Elk-1 using short-hairpin RNA (shRNA). Elk-1 overexpression rescued both the inhibitory effect of sorafenib on Mcl-1 expression and the cell killing effect of sorafenib. Furthermore, sorafenib reduced the stability of the Mcl-1 protein by enhancing its ubiquitination and degradation by the proteasome via the AKT/GSK3β and the ERK pathways. Similar results were detected in other EC cell lines. These results indicate that sorafenib induces apoptosis in EC cells by down-regulating the anti-apoptotic protein Mcl-1 via transcriptional inhibition and protein degradation. Our results thus support the notion that sorafenib may be used in endometrial cancer therapy. |
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Molecular Profile | Indication/Tumor Type | Response Type | Therapy Name | Approval Status | Evidence Type | Efficacy Evidence | References |
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Unknown unknown | endometrial carcinoma | not applicable | Sorafenib | Preclinical | Actionable | In preclinical studies, Nexavar (sorafenib) promoted apoptosis of endometrial carcinoma cells (PMID: 23463670). | 23463670 |