PMID- 25047426 OWN - NLM STAT- MEDLINE DCOM- 20150102 LR - 20211203 IS - 1879-0852 (Electronic) IS - 0959-8049 (Linking) VI - 50 IP - 14 DP - 2014 Sep TI - Hesperidin induces apoptosis and triggers autophagic markers through inhibition of Aurora-A mediated phosphoinositide-3-kinase/Akt/mammalian target of rapamycin and glycogen synthase kinase-3 beta signalling cascades in experimental colon carcinogenesis. PG - 2489-507 LID - S0959-8049(14)00757-6 [pii] LID - 10.1016/j.ejca.2014.06.013 [doi] AB - Abnormalities in the homeostasis mechanisms involved in cell survival and apoptosis are contributing factors for colon carcinogenesis. Interventions of these mechanisms by pharmacologically safer agents gain predominance in colon cancer prevention. We previously reported the chemopreventive efficacy of hesperidin against colon carcinogenesis. In the present study, we aimed at investigating the potential of hesperidin over the abrogated Aurora-A coupled pro-survival phosphoinositide-3-kinase (PI3K)/Akt signalling cascades. Further, the role of hesperidin over apoptosis and mammalian target of rapamycin (mTOR) mediated autophagic responses were studied. Azoxymethane (AOM) induced mouse model of colon carcinogenesis was involved in this study. Hesperidin treatment was provided either in initiation/post-initiation mode respectively. Hesperidin significantly altered AOM mediated anti-apoptotic scenario by modulating Bax/Bcl-2 ratio together with enhanced cytochrome-c release and caspase-3, 9 activations. In addition, hesperidin enhanced p53-p21 axis with concomitant decrease in cell cycle regulator. Hesperidin treatment caused significant up-regulation of tumour suppressor phosphatase and tensin homologue (PTEN) with a reduction in the expression of AOM mediated p-PI3K and p-Akt. Additionally, hesperidin administration exhibited inhibition against p-mTOR expression which in turn led to stimulation of autophagic markers Beclin-1 and LC3-II. Aurora-A an upstream regulator of PI3K/Akt pathway was significantly inhibited by hesperidin. Furthermore, hesperidin administration restored glycogen synthase kinase-3 beta (GSK-3beta) activity which in turn prevented the accumulation of oncoproteins beta-catenin, c-jun and c-myc. Taken together, hesperidin supplementation initiated apoptosis via targeted inhibition of constitutively activated Aurora-A mediated PI3K/Akt/GSK-3beta and mTOR pathways coupled with autophagic stimulation against AOM induced colon carcinogenesis. CI - Copyright (c) 2014 Elsevier Ltd. All rights reserved. FAU - Saiprasad, Gowrikumar AU - Saiprasad G AD - Department of Biochemistry, Cell Biology Laboratory, University of Madras, Guindy Campus, Chennai 600025, Tamil Nadu, India. FAU - Chitra, Palanivel AU - Chitra P AD - Department of Biochemistry, Cell Biology Laboratory, University of Madras, Guindy Campus, Chennai 600025, Tamil Nadu, India. FAU - Manikandan, Ramar AU - Manikandan R AD - Department of Zoology, University of Madras, Guindy Campus, Chennai 600025, Tamil Nadu, India. FAU - Sudhandiran, Ganapasam AU - Sudhandiran G AD - Department of Biochemistry, Cell Biology Laboratory, University of Madras, Guindy Campus, Chennai 600025, Tamil Nadu, India. Electronic address: sudhandiran@yahoo.com. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20140718 PL - England TA - Eur J Cancer JT - European journal of cancer (Oxford, England : 1990) JID - 9005373 RN - E750O06Y6O (Hesperidin) RN - EC 2.7.11.1 (Aurora Kinase A) RN - EC 2.7.11.1 (Glycogen Synthase Kinase 3 beta) RN - EC 2.7.11.1 (Gsk3b protein, mouse) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - EC 2.7.11.26 (Glycogen Synthase Kinase 3) SB - IM MH - Animals MH - Apoptosis/drug effects MH - Aurora Kinase A/*antagonists & inhibitors/metabolism MH - Autophagy/drug effects MH - Carcinogenesis/drug effects/metabolism MH - Colonic Neoplasms/*drug therapy/metabolism/pathology MH - Glycogen Synthase Kinase 3/*metabolism MH - Glycogen Synthase Kinase 3 beta MH - Hesperidin/*pharmacology MH - Male MH - Mice MH - Microscopy, Electron, Scanning MH - Phosphatidylinositol 3-Kinases/*metabolism MH - Signal Transduction/drug effects MH - TOR Serine-Threonine Kinases/*metabolism MH - Up-Regulation OTO - NOTNLM OT - Apoptosis OT - Aurora-A OT - Autophagy OT - Colon cancer OT - GSK-3beta OT - PI3K OT - mTOR EDAT- 2014/07/23 06:00 MHDA- 2015/01/03 06:00 CRDT- 2014/07/23 06:00 PHST- 2013/11/27 00:00 [received] PHST- 2014/02/17 00:00 [revised] PHST- 2014/06/16 00:00 [accepted] PHST- 2014/07/23 06:00 [entrez] PHST- 2014/07/23 06:00 [pubmed] PHST- 2015/01/03 06:00 [medline] AID - S0959-8049(14)00757-6 [pii] AID - 10.1016/j.ejca.2014.06.013 [doi] PST - ppublish SO - Eur J Cancer. 2014 Sep;50(14):2489-507. doi: 10.1016/j.ejca.2014.06.013. Epub 2014 Jul 18.