Abstract 2015: Lysophosphatidylcholine induces apoptosis via suppressing STAT3 and HDAC3 activities and binding to the Bcl-xL promoter in K562 chronic myelogenous leukemia cells

Abstract

Abstract Lysophosphatidylcholine (LPC) is a class of chemical compound which are derived from phosphatidylcholines usually isolated from the surface of wheat starch granules. In the present study, we investigated the molecular mechanisms responsible for LPC-induced apoptosis in chronic myeloid leukemia K562 cells. LPC exerted the inhibitory effect on the viability of K562 cells as well as other leukemic cell lines HL-60 and U937. Nonetheless, LPC significantly increased the acetylation of histone H3 at K18, 9 and 23 in K562 cells, but not in HL-60 and U937 cells. Consistently, LPC reduced histone deacetylase (HDAC) transcriptional activity and the expression of HDAC3 at protein level. LPC suppressed phosphorylation of mTOR and AKT, the upstream kinases of HDACs and induced p27 expression. We also found that LPC mediated inactivation of signal transducer and activator of transcription 3 (STAT3)-related signaling pathway in K562 cells, but not HL-60 and U937. LPC significantly inhibited phosphorylation and the DNA binding activity of STAT3, phosphorylation of Src and Janus activated kinase 2 (JAK2) as well as the expression of STAT3 target genes Cyclin D1, Cyclin E, Bcl-xL, Bcl-2, and Survivin at both protein and mRNA levels. LPC stimulated protein tyrosin phosphatases Src homology 2 domain-containing phosphatase 1 (SHP-1), but not SHP-2, SOCS-1 and PTEN. Blocking SHP-1 using sodium pervanadate or SHP-1 specific siRNA reversed LPC-mediated inactivation of STAT3 and HDAC and induction of apoptosis. Of importance, LPC blocked the nuclear translocation and interaction of HDAC3 and STAT3 as well as their binding onto the Bcl-xL promoter. Overall, our findings demonstrate that LPC has a potent anti-cancer activity through inducing apoptosis by suppressing HDAC3/STAT3 activation and binding to the Bcl-xL promoter in K562 cells. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2015. doi:1538-7445.AM2012-2015