FAK and HAS Inhibition Synergistically Decrease Colon Cancer Cell Viability and Affect Expression of Critical Genes
Vita M. Golubovskaya,
William G. Cance,
Kelli B. Dunn.
Focal adhesion kinase (FAK), hyaluronan (HA), and hyaluronan synthase-3 (HAS3) have been implicated in cancer growth
and progression. FAK inhibition with the small molecule inhibitor Y15 decreases colon cancer cell growth in vitro and in vivo. HAS3
inhibition in colon cancer cells decreases FAK expression and activation, and exogenous HA increases FAK activation. We sought to
determine the genes affected by HAS and FAK inhibition and hypothesized that dual inhibition would synergistically inhibit viability.
Y15 (FAK inhibitor) and the HAS inhibitor 4-methylumbelliferone (4-MU) decreased viability in a dose dependent manner; viability was
further inhibited by treatment with Y15 and 4-MU in colon cancer cells. HAS inhibited cells treated with 2μM of Y15 showed
significantly decreased viability compared to HAS scrambled cells treated with the same dose (p<0.05) demonstrating synergistic
inhibition of viability with dual FAK/HAS inhibition. Microarray analysis showed more than 2-fold up- or down-regulation of 121 genes
by HAS inhibition, and 696 genes by FAK inhibition (p<0.05) and revealed 29 common genes affected by both signaling. Among the
genes affected by FAK or HAS3 inhibition were genes, playing role in apoptosis, cell cycle regulation, adhesion, transcription, heatshock
and WNT pathways. Thus, FAK or HAS inhibition decreases SW620 viability and affects several similar genes, which are
involved in the regulation of tumor survival. Dual inhibition of FAK and HAS3 decreases viability to a greater degree than with either
agent alone, and suggests that synergistic inhibition of colon cancer cell growth can result from affecting similar genetic pathways.
Keywords: Colon cancer, FAK, Gene expression, Hyaluronan, Silenced RNA, Viability
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