Abstract
BackgroundAscites 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.MethodsUsing 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.ResultsIn 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.ConclusionsThese 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.
Highlights
Ascites may affect the progression of ovarian cancer (OC)
OC ascites upregulate Mcl-1 expression Previous studies have shown that OC ascites obtained from women with advanced disease attenuate TRAILinduced apoptosis [13,17], and ascites with prosurvival activity negatively affect progression-free survival [6]
One of the mechanisms by which ascites attenuate tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis in OC cells is through engagement of αvβ5 integrin and subsequent activation of Akt survival signaling pathway which results in the upregulation of caspase-8 inhibitor c-FLIPs [13,17]
Summary
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. The five-year survival of patients with late stage disease remains at < 30%, a figure that has not changed for the past 30 years [2]. This is related, at least in part, to the persistence of minimal residual disease after chemotherapy, which contributes to shorter progression-free survival [6,7]. Ascites create a protective environment for ovarian tumor cells that inhibit druginduced apoptosis (de novo resistance) [13,17]. It is important to define the contribution of each pathway both to fully understand cell survival signaling and to validate individual pathways as therapeutic targets
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