Abstract 3094: Sprouty and cell proliferation in colorectal cancer

Abstract

Abstract BACKGROUND & AIMS: Sprouty (SPRY) proteins are evolutionarily conserved modulators of mitogen-activated protein kinase pathway. SPRY2 appears to function as a tumor suppressor in other cancers, whereas we reported that SPRY2 functions as an oncogene in colorectal cancer (CRC). To further understand the oncogenic potential of SPRY1 and SPRY2 in CRC, we investigated the mechanisms by which these proteins regulate cell proliferation in CRC. MATERIALS & METHODS: Human CRC cDNA arrays were employed to assess mRNA levels of SPRY1, SPRY2 and p21. SPRY1 and SPRY2 were knocked-down in CaCo2 colon cancer cells by siRNA. Effects of SPRY were assessed by immunoblotting, real time PCR, luciferase reporter assay, and confocal microscopy. Mouse embryonic fibroblasts (MEFs) derived from SPRY mutant mice were utilized to dissect SPRY functions in mesenchymal cells. RESULTS: In this study, surprisingly, we present evidence to suggest that concomitant activation of ERK, p-38 and AKT signaling cascades is insufficient to drive cancer cell proliferation in SPRY modulated cells. Suppression of SPRY in colon cancer cells upregulates p21, a cell cycle inhibitor. SPRY2 dependent p21 promoter activation may account for upregulation of p21 expression and inhibition of cancer cell proliferation. Underscoring the biological relevance of these findings, recombination of floxed SPRY1 and SPRY2 alleles in mouse embryonic fibroblasts (MEFs) resulted in increased expression of p21. Finally, in a human CRC cDNA array we established an inverse correlation of SPRY1 and SPRY2 with p21 mRNA expression. CONCLUSIONS: Together, this study indicates that SPRY is a target of therapeutic intervention in CRC. Citation Format: Qiong Zhang, Katherine Shim, Kevin Wright, Alexander Jurkevich, Sharad Khare. Sprouty and cell proliferation in colorectal cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3094. doi:10.1158/1538-7445.AM2015-3094