Ovarian cancer ascites increase Mcl-1 expression in tumor cells through ERK1/2-Elk-1 signaling to attenuate TRAIL-induced apoptosis
<p>Abstract</p> <p>Background</p> <p>Ascites may affect the progression of ovarian cancer (OC). In particular, soluble factors present in OC ascites can create a protective environment for tumor cells that promote <it>de novo</it> resistance to drug- and dea...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2012-11-01
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| Series: | Molecular Cancer |
| Subjects: | |
| Online Access: | http://www.molecular-cancer.com/content/11/1/84 |
| _version_ | 1811251240499150848 |
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| author | Goncharenko-Khaider Nadzeya Matte Isabelle Lane Denis Rancourt Claudine Piché Alain |
| author_facet | Goncharenko-Khaider Nadzeya Matte Isabelle Lane Denis Rancourt Claudine Piché Alain |
| author_sort | Goncharenko-Khaider Nadzeya |
| collection | DOAJ |
| description | <p>Abstract</p> <p>Background</p> <p>Ascites may affect the progression of ovarian cancer (OC). In particular, soluble factors present in OC ascites can create a protective environment for tumor cells that promote <it>de novo</it> resistance to drug- and death receptor-induced apoptosis. However, the underlying molecular mechanisms responsible for ascites-induced drug resistance are not well characterized.</p> <p>Methods</p> <p>Using human OC cell lines and tissues microarrays of human OC biopsies, we assessed the mechanism by which OC ascites increase Mcl-1 expression using Western blots, chemical inhibitors of ERK and small-inhibitory RNA treatments.</p> <p>Results</p> <p>In the present study, we found that both Mcl-1 mRNA and protein levels were upregulated within 2 h upon treatment of OC cells with ascites obtained from women with advanced OC. In contrast, the expression of other Bcl-2 family antiapoptotic members such as Bcl-2 and Bcl-X<sub>L</sub> was not affected by ascites. An increase of Mcl-1 expression was consistently observed across different ascites from women with advanced serous OC. The knockdown of Mcl-1 significantly blocked ascites-induced Mcl-1 upregulation and ascites-mediated inhibition of TRAIL-induced apoptosis. Ascites induced a rapid phosphorylation of ERK1/2 and Elk-1 transcription factor. Furthermore, we found that ERK1/2 inhibition or Elk-1 knockdown was sufficient to block ascites-induced Mcl-1 expression. In high grade serous OC, we found a positive correlation between phosphorylated ERK1/2 and Mcl-1 expression.</p> <p>Conclusions</p> <p>These results indicate that ascites-induced ERK1/2/Elk-1 signaling is critical for Mcl-1 expression and for the ascites-mediated attenuation of TRAIL-induced apoptosis. The ERK1/2/Elk-1/Mcl-1 pathway represents a novel mechanism by which ascites induce <it>de novo</it> TRAIL resistance in OC cells.</p> |
| first_indexed | 2024-04-12T16:16:50Z |
| format | Article |
| id | doaj.art-c668fb4891a94057b5e1c8f2bc52b9a3 |
| institution | Directory Open Access Journal |
| issn | 1476-4598 |
| language | English |
| last_indexed | 2024-04-12T16:16:50Z |
| publishDate | 2012-11-01 |
| publisher | BMC |
| record_format | Article |
| series | Molecular Cancer |
| spelling | doaj.art-c668fb4891a94057b5e1c8f2bc52b9a32022-12-22T03:25:42ZengBMCMolecular Cancer1476-45982012-11-011118410.1186/1476-4598-11-84Ovarian cancer ascites increase Mcl-1 expression in tumor cells through ERK1/2-Elk-1 signaling to attenuate TRAIL-induced apoptosisGoncharenko-Khaider NadzeyaMatte IsabelleLane DenisRancourt ClaudinePiché Alain<p>Abstract</p> <p>Background</p> <p>Ascites may affect the progression of ovarian cancer (OC). In particular, soluble factors present in OC ascites can create a protective environment for tumor cells that promote <it>de novo</it> resistance to drug- and death receptor-induced apoptosis. However, the underlying molecular mechanisms responsible for ascites-induced drug resistance are not well characterized.</p> <p>Methods</p> <p>Using human OC cell lines and tissues microarrays of human OC biopsies, we assessed the mechanism by which OC ascites increase Mcl-1 expression using Western blots, chemical inhibitors of ERK and small-inhibitory RNA treatments.</p> <p>Results</p> <p>In the present study, we found that both Mcl-1 mRNA and protein levels were upregulated within 2 h upon treatment of OC cells with ascites obtained from women with advanced OC. In contrast, the expression of other Bcl-2 family antiapoptotic members such as Bcl-2 and Bcl-X<sub>L</sub> was not affected by ascites. An increase of Mcl-1 expression was consistently observed across different ascites from women with advanced serous OC. The knockdown of Mcl-1 significantly blocked ascites-induced Mcl-1 upregulation and ascites-mediated inhibition of TRAIL-induced apoptosis. Ascites induced a rapid phosphorylation of ERK1/2 and Elk-1 transcription factor. Furthermore, we found that ERK1/2 inhibition or Elk-1 knockdown was sufficient to block ascites-induced Mcl-1 expression. In high grade serous OC, we found a positive correlation between phosphorylated ERK1/2 and Mcl-1 expression.</p> <p>Conclusions</p> <p>These results indicate that ascites-induced ERK1/2/Elk-1 signaling is critical for Mcl-1 expression and for the ascites-mediated attenuation of TRAIL-induced apoptosis. The ERK1/2/Elk-1/Mcl-1 pathway represents a novel mechanism by which ascites induce <it>de novo</it> TRAIL resistance in OC cells.</p>http://www.molecular-cancer.com/content/11/1/84Ovarian cancerResistanceMcl-1ERK1/2TRAILElk-1 |
| spellingShingle | Goncharenko-Khaider Nadzeya Matte Isabelle Lane Denis Rancourt Claudine Piché Alain Ovarian cancer ascites increase Mcl-1 expression in tumor cells through ERK1/2-Elk-1 signaling to attenuate TRAIL-induced apoptosis Molecular Cancer Ovarian cancer Resistance Mcl-1 ERK1/2 TRAIL Elk-1 |
| title | Ovarian cancer ascites increase Mcl-1 expression in tumor cells through ERK1/2-Elk-1 signaling to attenuate TRAIL-induced apoptosis |
| title_full | Ovarian cancer ascites increase Mcl-1 expression in tumor cells through ERK1/2-Elk-1 signaling to attenuate TRAIL-induced apoptosis |
| title_fullStr | Ovarian cancer ascites increase Mcl-1 expression in tumor cells through ERK1/2-Elk-1 signaling to attenuate TRAIL-induced apoptosis |
| title_full_unstemmed | Ovarian cancer ascites increase Mcl-1 expression in tumor cells through ERK1/2-Elk-1 signaling to attenuate TRAIL-induced apoptosis |
| title_short | Ovarian cancer ascites increase Mcl-1 expression in tumor cells through ERK1/2-Elk-1 signaling to attenuate TRAIL-induced apoptosis |
| title_sort | ovarian cancer ascites increase mcl 1 expression in tumor cells through erk1 2 elk 1 signaling to attenuate trail induced apoptosis |
| topic | Ovarian cancer Resistance Mcl-1 ERK1/2 TRAIL Elk-1 |
| url | http://www.molecular-cancer.com/content/11/1/84 |
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