Ovarian cancer ascites increase Mcl-1 expression in tumor cells through ERK1/2-Elk-1 signaling to attenuate TRAIL-induced apoptosis

• Published in: Molecular cancer Vol. 11; no. 1; p. 84
• Main Authors: Goncharenko-Khaider, Nadzeya, Matte, Isabelle, Lane, Denis, Rancourt, Claudine, Piché, Alain
• Format: Journal Article
• Language: English
• Published: England BioMed Central 17-11-2012; BMC
• Subjects: Apoptosis - genetics; Ascites - genetics; Ascites - metabolism; Cancer; Cell Line, Tumor; Cells; Elk-1; ERK1/2; ets-Domain Protein Elk-1 - metabolism; Female; Focal Adhesion Kinase 1 - metabolism; Gene Expression Regulation, Neoplastic; Humans; Mcl-1; Medical research; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinase 3 - metabolism; Myeloid Cell Leukemia Sequence 1 Protein; Neoplasm Grading; Ovarian cancer; Ovarian Neoplasms - genetics; Ovarian Neoplasms - metabolism; Ovarian Neoplasms - pathology; Proto-Oncogene Proteins c-bcl-2 - genetics; Proto-Oncogene Proteins c-bcl-2 - metabolism; Resistance; Signal Transduction; TNF-Related Apoptosis-Inducing Ligand - metabolism; TRAIL
• DOI: 10.1186/1476-4598-11-84
• EISSN: 1476-4598

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 de novo resistance to drug- and death receptor-induced apoptosis. However, the underlying molecular mechanisms responsible for ascites-induced drug resistance are not well characterized.
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.
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-XL 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.
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 de novo TRAIL resistance in OC cells.