title: CCT128930 induces cell cycle arrest, DNA damage, and autophagy independent of Akt inhibition.
abstract: PI3K/Akt/mTOR pathway plays an important role in tumor progression and anti-cancer drug resistance. The aim of the present study is to determine the antitumor effect of CCT128930, a novel small molecule inhibitor of Akt, in the HepG2 hepatoma cancer cells. Our results showed that at low concentrations, CCT128930 increased, but not inhibited, the phosphorylation of Akt in HepG2 and A549 cells. CCT128930 inhibited cell proliferation by inducing cell cycle arrest in G1 phase through downregulation of cyclinD1 and Cdc25A, and upregulation of p21, p27 and p53. A higher dose (20 μM) of CCT128930 triggered cell apoptosis with activation of caspase-3, caspase-9, and PARP. Treatment with CCT128930 increased phosphorylation of ERK and JNK in HepG2 cells. CCT128930 activated DNA damage response of HepG2 cell characterized by phosphorylation of H2AX, ATM (ataxia-telangiectasia mutated), Chk1 and Chk2. Upon exposure to CCT128930 at a higher concentration, HepG2 cells exhibited autophagy was accompanied by an increase the levels of LC3-II and Beclin-1. Blocking autophagy using chloroquine magnified CCT128930-induced apoptotic cell death and the phosphorylation of H2AX. The results in this study have advanced our current understandings of the anti-cancer mechanisms of CCT128930 in cancer cells.
authors.affiliation: School of Biological Science, Taishan Medical University, Taian 271016, PR China; Key Lab of Cerebral Microcirculation in Universities of Shandong, Taishan Medical University, Taian 271000, PR China.
authors.forename: Feng-Ze
authors.initials: FZ
authors.lastname: Wang
authors.affiliation: School of Biological Science, Taishan Medical University, Taian 271016, PR China.
authors.forename: Zheng-Yao
authors.initials: ZY
authors.lastname: Chang
authors.affiliation: School of Pharmacology, Taishan Medical University, Taian 271016, PR China.
authors.forename: Hong-Rong
authors.initials: HR
authors.lastname: Fei
authors.affiliation: Key Lab of Cerebral Microcirculation in Universities of Shandong, Taishan Medical University, Taian 271000, PR China.
authors.forename: Ming-Feng
authors.initials: MF
authors.lastname: Yang
authors.affiliation: Key Lab of Cerebral Microcirculation in Universities of Shandong, Taishan Medical University, Taian 271000, PR China.
authors.forename: Xiao-Yi
authors.initials: XY
authors.lastname: Yang
authors.affiliation: Key Lab of Cerebral Microcirculation in Universities of Shandong, Taishan Medical University, Taian 271000, PR China; Department of Neurology, Affiliated Hospital of Taishan Medical University, Taian, Shandong 271000, China. Electronic address: baoliangsunty@gmail.com.
authors.forename: Bao-Liang
authors.initials: BL
authors.lastname: Sun
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D002738:Chloroquine / Q000494:pharmacology; D004249:DNA Damage; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects*; D056945:Hep G2 Cells; D006657:Histones / Q000378:metabolism; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology*; D011758:Pyrroles / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: C561680:4-(4-chlorobenzyl)-1-(7H-pyrrolo(2,3-d)pyrimidin-4-yl)piperidin-4-amine; D000970:Antineoplastic Agents; D006657:Histones; D011743:Pyrimidines; D011758:Pyrroles; D002738:Chloroquine; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases
keywords: Akt; Autophagy; CCT128930; Cell cycle; DNA damage