Thomas Jefferson University, USA
Aejaz Sayeed received his Ph.D. in Immunology in the year 2000. He undertook his post doctoral training in cancer biology and since then he has acquired a broadbased interdisciplinary oncology training with particular expertise in preclinical tumor models of breast and prostate cancer. Using novel primary culture model systems, He studied molecular signatures associated with different histological grades of human breast cancer. He joined TJU as a faculty in 2010 and his current research is focused on understanding the role of integrins and growth factor receptors in radiation resistance of prostate cancer.
Radiation therapy remains an important modality for cancer treatment and ongoing research efforts focus on overcoming radiation resistance to improve patient survival. Here we show that fractionated radiation, 10 Gy for 5 consecutive days (50 Gy total), effectively blocks prostate tumor growth in transgenic adenocarcinoma of mouse prostate (TRAMP) mice. We have previously shown that b1 integrins suppress c-Jun amino-terminal kinase 1 (JNK1) which plays a crucial role in promoting radiation-induced apoptosis in both cancer cells and in the TRAMP model. Using a selective and reversible JNK-1, -2 and -3 inhibitor (SP600125), we demonstrate that the conditional ablation of b1 integrins in the prostatic epithelium of TRAMP mice in conjunction with JNK inhibition promotes resistance to radiation as observed in increased tumor growth. While radiation effectively suppresses tumor development in sham-treated b1 null mice, blocking JNK signaling offsets the effect of radiation resulting in increased tumor growth. We demonstrate that a prominent feature associated with tumor progression driven by JNK inhibition is the up-regulation of Focal Adhesion Kinase (FAK) signaling (enhanced levels of total and phosphorylated protein) in TRAMP prostate tumors. The JNK pathway is not active in irradiated β1 wild type TRAMP mice; as expected, upon JNK inhibition neither FAK upregulation nor tumor growth is observed. We also demonstrate that b1 integrins and FAK are found in exosomes released from prostate cancer cells, suggesting novel means of acquiring resistant phenotypes. Our study delineates a b1 integrin/JNK/FAK signaling pathway of radiation resistance in prostate cancer and identifies potential targets for facilitating development of radiosensitizing therapy against PrCa.