Gambogic acid induces G0/G1 arrest and apoptosis involving inhibition of SRC-3 and inactivation of Akt pathway in K562 leukemia cells.
Gambogic acid (GA), a major active component of gamboge, exhibits potent anticancer activity in many kinds of cancer cells. However, the anticancer mechanism of GA is not clearly understood. Here we showed that GA could cause growth inhibition, induce the G0/G1 phase cell cycle arrest and apoptosis in human chronic myelogenous leukemia cell line K562 cells. Since steroid receptor coactivator-3 (SRC-3), overexpressed in many human malignancies including leukemia, is a central target for cancer therapy, we also explored the effects of GA on SRC-3 and SRC-3-regulated gene products in K562. GA treatment downregulated the expression of SRC-3 and then inhibited the activity of Akt kinase and its downstream targets p70 S6 kinase 1 (S6K1) and glycogen synthase kinase 3beta (GSK3beta) without changes in total protein levels of these three proteins, which thus influenced the expression of the apoptosis related gene Bcl-2 in K562 cells. These results suggest that GA might exhibit its strong antitumor effects via the interruption of SRC-3.
Department of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
Rui
R
Li
Yan
Y
Chen
Ling-Lan
LL
Zeng
Wen-Xiu
WX
Shu
Fei
F
Zhao
Lu
L
Wen
Yuan
Y
Liu
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002467:Cell Nucleus / Q000187:drug effects / Q000648:ultrastructure; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D015536:Down-Regulation; D004354:Drug Screening Assays, Antitumor; D015870:Gene Expression / Q000187:drug effects; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D051548:Histone Acetyltransferases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007399:Interphase / Q000187:drug effects* / Q000502:physiology; D020014:K562 Cells; D007951:Leukemia, Myeloid / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D056921:Nuclear Receptor Coactivator 3; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D044004:Xanthones / Q000494:pharmacology*
D000970:Antineoplastic Agents; D015534:Trans-Activators; D044004:Xanthones; C052659:gambogic acid; D051548:Histone Acetyltransferases; C538866:NCOA3 protein, human; D056921:Nuclear Receptor Coactivator 3; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D051057:Proto-Oncogene Proteins c-akt; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D038362:Glycogen Synthase Kinase 3