title: Idelalisib induces PUMA-dependent apoptosis in colon cancer cells.
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.
authors.affiliation: Department of Laboratory Medicine, The People's Hospital of Liaoning Province, Shenyang, China.
authors.forename: Shida
authors.initials: S
authors.lastname: Yang
authors.affiliation: Department of Orthopedics, The People's Hospital of Liaoning Province, Shenyang, China.
authors.forename: Zhiyong
authors.initials: Z
authors.lastname: Zhu
authors.affiliation: Department of Laboratory Medicine, The People's Hospital of Liaoning Province, Shenyang, China.
authors.forename: Xiaobing
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Laboratory Medicine, The First Affiliated Hospital of Liaoning University of Traditional Chinese Medicine, Shenyang, China.
authors.forename: Ning
authors.initials: N
authors.lastname: Zhang
authors.affiliation: Department of Neurology, The People's Hospital of Liaoning Province, Shenyang, China.
authors.forename: Zhicheng
authors.initials: Z
authors.lastname: Yao
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000494:pharmacology; D051017:Apoptosis Regulatory Proteins / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D004357:Drug Synergism; D005472:Fluorouracil / Q000008:administration & dosage / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D000071679:Glycogen Synthase Kinase 3 beta / Q000378:metabolism; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D051379:Mice; D010671:Phenylurea Compounds / Q000008:administration & dosage / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D011687:Purines / Q000008:administration & dosage* / Q000494:pharmacology; D011725:Pyridines / Q000008:administration & dosage / Q000494:pharmacology; D052999:Quinazolinones / Q000008:administration & dosage* / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D019892:eIF-2 Kinase / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; C438378:BBC3 protein, human; D010671:Phenylurea Compounds; D011518:Proto-Oncogene Proteins; D011687:Purines; D011725:Pyridines; D052999:Quinazolinones; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C559147:regorafenib; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D019892:eIF-2 Kinase; D005472:Fluorouracil; C552946:idelalisib
keywords: GSK3β; PUMA; apoptosis; colon cancer; idelalisib