Idelalisib induces PUMA-dependent apoptosis in colon cancer cells

// Shida Yang 1 , Zhiyong Zhu 3 , Xiaobing Zhang 1 , Ning Zhang 4 , Zhicheng Yao 2 1 Department of Laboratory Medicine, The People’s Hospital of Liaoning Province, Shenyang, China 2 Department of Neurology, The People’s Hospital of Liaoning Province, Shenyang, China 3 Department of Orthopedics, The People’s Hospital of Liaoning Province, Shenyang, China 4 Department of Laboratory Medicine, The First Affiliated Hospital of Liaoning University of Traditional Chinese Medicine, Shenyang, China Correspondence to: Zhicheng Yao, email: yangshidasy1@gmail.com Keywords: idelalisib, colon cancer, PUMA, apoptosis, GSK3β Received: July 29, 2016      Accepted: December 12, 2016      Published: December 20, 2016 ABSTRACT Idelalisib, a PI3K inhibitor, specifically targeting p110δ, has been approved for the treatment of chronic lymphocytic leukemia/small lymphocytic lymphoma and follicular lymphoma. However, the mechanisms of action of idelalisib in colon cancer cells are not well understood. We investigated how idelalisib suppresses colon cancer cells growth and potentiates effects of other chemotherapeutic drugs. In this study, we found that idelalisib treatment induces PUMA in colon cancer cells irrespective of p53 status through the p65 pathway following AKT inhibition and glycogen synthase kinase 3β (GSK3β) activation. PUMA is necessary for idelalisib-induced apoptosis in colon cancer cells. Idelalisib also synergized with 5-FU or regorafenib to induce marked apoptosis via PUMA in colon cancer cells. Furthermore, PUMA deficiency suppressed apoptosis and antitumor effect of idelalisib in xenograft model. These results demonstrate a critical role of PUMA in mediating the anticancer effects of idelalisib in colon cancer cells and suggest that PUMA induction can be used as an indicator of idelalisib sensitivity, and also have important implications for it clinical applications.