The engagement of integrins to the extra cellular matrix components triggers a signaling cascade that leads to the activation of focal adhesion selleck chemicals kinase, one of the Inhibitors,Modulators,Libraries earliest events that immediately follows integrin ECM component engagement. In this Inhibitors,Modulators,Libraries context, we previously showed that ascites induce a rapid FAK activation. Thus, we assessed whether FAK was involved in ascites mediated activation of ERK1/2/Elk 1 signaling. To this end, CaOV3 and OVCAR3 cells were transfected with FAK or control siRNA and cells were treated with ascites. Figure 6 shows that siRNA mediated FAK knockdown inhibited ascites induced Akt activation as we have previously reported. In contrast, ERK1/2 activation was not affected by FAK knockdown. Consistent with this obser vation, Elk 1 activation and Mcl 1 expression remained unaffected by FAK knockdown.

These data suggest that integrin/FAK signaling is Inhibitors,Modulators,Libraries not critical for Mcl 1 upregulation. Activated ERK1/2 correlates with Mcl 1 expression in high grade serous OC To determine whether our in vitro findings were clinic ally relevant in human ovarian tumors, we assessed if the ERK1/2 dependent regulation of Mcl 1 expression in CaOV3 and OVCAR3 cell lines correlated in HGSOC, the most common subtype of OC. We initially per formed a pilot study on 20 HGSOC samples to deter mine the optimal conditions for antibody staining against Mcl 1, phospho ERK1/2 and phospho Elk 1. Despite several attempts, we were unable to obtained consistent staining for phospho Elk 1.

Based upon this pilot study, we examined the relationship between phos pho ERK1/2 and Mcl 1 expression in a tissue microarray of HGSOC provided by the Pan canadian plat form for the development of biomarker driven subtype specific management of ovarian carcinoma. The TMA consisted of 120 HGSOC samples and each tumor was Inhibitors,Modulators,Libraries represented by two separate spots on the TMA. The immunostaining was scored using a 0 3 scoring system. Representative images from the sampled tumors demonstrate that regions within individual section expressing Mcl 1 also Inhibitors,Modulators,Libraries have positive phospho ERK1/2 staining. The data was analyzed by plotting the scores as an XY scatter and performing a Spearman correlation test. We found a statistically significant positive correlation between the phosphorylation of ERK1/2 and Mcl 1 expres sion. The tumors were separated into two groups based on the median Mcl 1 H score of 62.

5. Samples with a score 62. 5 were classified as low Mcl 1 and those with a score 62. 5 were classified as high Mcl 1. The median phospho ERK1/2 for the low Mcl 1 group was 12 and the median for the high Mcl 1 group was 46, a difference that was statistically significant using a Mann Whitney test. These data sup port the regulation of Mcl 1 expression by selleck catalog the ERK1/2 pathway in HGSOC. Discussion The development of resistance to chemotherapy remains a major problem with OC.