Targeting PI3K and RAD51 in Barrett’s Adenocarcinoma: Impact on DNA Damage Checkpoints, Expression Profile and Tumor Growth

Cancer Genomics - Proteomics

Pierfrancesco Tassone⁴  Yu-Tzu Tai⁵  Jagannath Pal¹  Masood A. Shammas¹  Nikhil C. Munshi²  Leutz Buon³  Puru Nanjappa¹  Mariateresa Fulciniti² 

[1] Department of Adult Oncology, Harvard (Dana Farber) Cancer Institute, Boston, MA, U.S.A.Department of Medicine, VA Health Care System, Boston, MA, U.S.A.Department of Adult Oncology, Harvard (Dana Farber) Cancer Institute, Boston, MA, U.S.A.Department of Adult Oncology, Harvard (Dana Farber) Cancer Institute, Boston, MA, U.S.A.Department of Medicine, VA Health Care System, Boston, MA, U.S.A.Department of Medicine, VA Health Care System, Boston, MA, U.S.A.Department of Adult Oncology, Harvard (Dana Farber) Cancer Institute, Boston, MA, U.S.A.Department of Medicine, VA Health Care System, Boston, MA, U.S.A.;Department of Adult Oncology, Harvard (Dana Farber) Cancer Institute, Boston, MA, U.S.A.Department of Medicine, VA Health Care System, Boston, MA, U.S.A.Department of Medicine, Harvard Medical School, Boston, MA, U.S.A.Department of Adult Oncology, Harvard (Dana Farber) Cancer Institute, Boston, MA, U.S.A.Department of Adult Oncology, Harvard (Dana Farber) Cancer Institute, Boston, MA, U.S.A.Department of Medicine, VA Health Care System, Boston, MA, U.S.A.Department of Medicine, Harvard Medical School, Boston, MA, U.S.A.Department of Medicine, VA Health Care System, Boston, MA, U.S.A.Department of Adult Oncology, Harvard (Dana Farber) Cancer Institute, Boston, MA, U.S.A.Department of Medicine, VA Health Care System, Boston, MA, U.S.A.Department of Medicine, Harvard Medical School, Boston, MA, U.S.A.Department of Medicine, Harvard Medical School, Boston, MA, U.S.A.Department of Adult Oncology, Harvard (Dana Farber) Cancer Institute, Boston, MA, U.S.A.Department of Medicine, VA Health Care System, Boston, MA, U.S.A.Department of Medicine, Harvard Medical School, Boston, MA, U.S.A.;Department of Adult Oncology, Harvard (Dana Farber) Cancer Institute, Boston, MA, U.S.A.Department of Adult Oncology, Harvard (Dana Farber) Cancer Institute, Boston, MA, U.S.A.Department of Adult Oncology, Harvard (Dana Farber) Cancer Institute, Boston, MA, U.S.A.;Magna Graecia University and Tommaso Campanella Cancer Center, Catanzaro, ItalyMagna Graecia University and Tommaso Campanella Cancer Center, Catanzaro, ItalyMagna Graecia University and Tommaso Campanella Cancer Center, Catanzaro, Italy;Department of Adult Oncology, Harvard (Dana Farber) Cancer Institute, Boston, MA, U.S.A.Department of Medicine, Harvard Medical School, Boston, MA, U.S.A.Department of Adult Oncology, Harvard (Dana Farber) Cancer Institute, Boston, MA, U.S.A.Department of Adult Oncology, Harvard (Dana Farber) Cancer Institute, Boston, MA, U.S.A.Department of Medicine, Harvard Medical School, Boston, MA, U.S.A.Department of Medicine, Harvard Medical School, Boston, MA, U.S.A.Department of Adult Oncology, Harvard (Dana Farber) Cancer Institute, Boston, MA, U.S.A.Department of Medicine, Harvard Medical School, Boston, MA, U.S.A.

关键词: Barrett’s adenocarcinoma;    RAD51;    DNA damage;    phosphoinositide 3-kinase;    wortmannin;    BAC cell line;    FLO-1 cells;    OE33 cells;   

DOI  :  

来源: Delinasios GJ CO

【 摘 要 】

Phosphatidylinositol 3-kinase (PI3K)/v-akt murine thymoma viral oncogene homolog 1 (AKT) signaling in cancer is implicated in various survival pathways including regulation of recombinase (RAD51). In this study, we evaluated PI3K and RAD51 as targets in Barrett’s adenocarcinoma (BAC) cells both in vitro and in vivo. BAC cell lines (OE19, OE33, and FLO-1) were cultured in the presence of PI3K inhibitor (wortmannin) and the impact on growth and expression of AKT, phosphorylated-AKT (P-AKT), and RAD51 was determined. Wortmannin induced growth arrest and apoptosis in two BAC cell lines (OE33 and OE19), which had relatively higher expression of AKT. FLO-1 cells, with lower AKT expression, were less sensitive to treatment and investigated further. In FLO-1 cells, wortmannin suppressed ataxia telangiectasia and Rad3-related protein (ATR)-checkpoint kinase 1 (CHK1)-mediated checkpoint and multiple DNA repair genes, whereas RAD51 and CHK2 were not affected. Western blotting confirmed that RAD51 was suppressed by wortmannin in OE33 and OE19 cells, but not in FLO-1 cells. Suppression of RAD51 in FLO-1 cells down-regulated the expression of CHK2 and CHK1, and reduced the proliferative potential. Finally, the suppression of RAD51 in FLO-1 cells, significantly increased the anticancer activity of wortmannin in these cells, both in vitro and in vivo. We show that PI3K signaling and hsRAD51, through distinct roles in DNA damage response and repair pathways, provide survival advantage to BAC cells. In cells with inherent low expression of AKT, RAD51 is unaffected by PI3K suppression and provides an additional survival pathway. Simultaneous suppression of PI3K and RAD51, especially in cells with lower AKT expression, can significantly reduce their proliferative potential.

【 授权许可】

Unknown