title: Inactivation of HDAC3 and STAT3 is critically involved in 1-stearoyl-sn-glycero-3-phosphocholine-induced apoptosis in chronic myelogenous leukemia K562 cells.
abstract: We here investigated the anticancer mechanism of 1-stearoyl-sn-glycero-3-phosphocholine (LPC), one of the lysophosphatidylcholines, in chronic myelogenous leukemia (CML) K562 cells. LPC significantly showed cytotoxicity at 80 μM and induced apoptosis by sub-G1 accumulation, increase in Annexin V positive and caspase activation. LPC enhanced histone H3 acetylation but decreased histone deacetylase (HDAC) activity and HDAC3 expression. LPC also inhibited phosphorylation of STAT3, its DNA binding activity and nuclear co-localization of HDAC3 and STAT3. In addition, LPC effectively attenuated the expression of survival genes such as Cyclin D1, Cyclin E, Bcl-xL, Bcl-2 and survivin but did not affect COX-2 expression in K562 cells. Furthermore, LPC suppressed phosphorylation of Src and Janus activated kinase 2 while promoted the expression of tyrosine phosphatase Src homology 2 domain-containing phosphatase 1 (SHP-1). Consistently, silencing SHP-1 and pervanadate, an inhibitor of protein tyrosine phosphatase, reversed inactivation of HDAC and STAT3, cleavages of caspase 3 and poly (ADP-ribose) polymerase in LPC-induced apoptosis. Of note, chromatin immunoprecipitation assay revealed that LPC suppressed the binding of HDAC3 and STAT3 to Bcl-xL, Bcl-2 and survivin promoter. Overall, our findings indicate that inactivation of STAT3 and HDAC mediates LPC-induced apoptosis in CML K562 cells.
authors.affiliation: Cancer Preventive Material Development Research Center, College of Oriental Medicine, Kyung Hee University, 1 Hoegi-dong, Dongdaemun-gu, Seoul, 131-701, South Korea.
authors.forename: Ji Hoon
authors.initials: JH
authors.lastname: Jung
authors.forename: Soo-Jin
authors.initials: SJ
authors.lastname: Jeong
authors.forename: Ji-Hyun
authors.initials: JH
authors.lastname: Kim
authors.forename: Sung-Ki
authors.initials: SK
authors.lastname: Jung
authors.forename: Deok-Beom
authors.initials: DB
authors.lastname: Jung
authors.forename: Duckgu
authors.initials: D
authors.lastname: Lee
authors.forename: Eun Jung
authors.initials: EJ
authors.lastname: Sohn
authors.forename: Miyong
authors.initials: M
authors.lastname: Yun
authors.forename: Hyo-Jung
authors.initials: HJ
authors.lastname: Lee
authors.forename: Hyo-Jeong
authors.initials: HJ
authors.lastname: Lee
authors.forename: Sung-Hoon
authors.initials: SH
authors.lastname: Kim
mesh_terms: D000107:Acetylation; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D018922:HL-60 Cells; D006655:Histone Deacetylases / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D006801:Humans; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000378:metabolism / Q000473:pathology; D008244:Lysophosphatidylcholines / Q000633:toxicity*; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D051020:bcl-X Protein / Q000235:genetics / Q000378:metabolism; D000099186:Histone Deacetylase 3
chemical_list: D006655:Histone Deacetylases; D006657:Histones; D008244:Lysophosphatidylcholines; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D034741:RNA, Small Interfering; D050796:STAT3 Transcription Factor; D051020:bcl-X Protein; D000099186:Histone Deacetylase 3; C026564:stearoyl alpha-lysolecithin; C509249:PTPN6 protein, human