LukS‐PV induces apoptosis in acute myeloid leukemia cells mediated by C5a receptor

• Main Authors: Peng Zhang, Wen‐Wei Yu, Jing Peng, Liang‐Fei Xu, Chang‐Cheng Zhao, Wen‐Jiao Chang, Xiao‐Ling Ma
• Format: Article
• Language: English
• Published: Wiley 2019-05-01
• Series: Cancer Medicine
• Subjects: AML; C5a receptor; LukS‐PV; molecular marker; therapeutic target
• Online Access: https://doi.org/10.1002/cam4.2137

Abstract LukS‐PV is one of the two components of Panton‐Valentine leucocidin (PVL). Our previous study showed that LukS‐PV can induce apoptosis in human acute myeloid leukemia (AML) THP‐1 and HL‐60 cells. C5aR (C5a receptor) is the receptor for PVL, but whether C5aR plays a key role in LukS‐PV induced apoptosis is unclear. The aim of this study was to establish whether C5aR plays a physiological role in apoptosis of leukemia cells induced by LukS‐PV. We investigated the role of C5aR in leukemia cell apoptosis induced by LukS‐PV by pretreatment of THP‐1 and HL‐60 cells with C5aR antagonist and transfection to knockdown C5aR in THP‐1 cells or overexpress C5aR in Jurkat cells before treatment with LukS‐PV. Cell apoptosis was analyzed by staining with Annexin V/propidium iodide or Annexin V‐PE/7‐AAD. Mitochondrial membrane potential (MMP) was determined using JC‐1 dye. The expression of apoptosis‐associated genes and proteins was identified by qRT‐polymerase chain reaction and Western blotting analysis, respectively. As the C5aR antagonist concentration increased, the rate of apoptosis induced by LukS‐PV decreased, the MMP increased, and expression of pro‐apoptotic Bax and Bak genes and proteins was downregulated while that of anti‐apoptotic Bcl‐2 and Bcl‐x genes and proteins was upregulated. Knockdown of C5aR also decreased LukS‐PV–induced THP‐1 cell apoptosis. LukS‐PV did not induce apoptosis of Jurkat cells, which have no endogenous C5aR expression; however, LukS‐PV did induce apoptosis in Jurkat cells after overexpression of C5aR. Correspondingly, the MMP decreased and Bax and Bak were upregulated while Bcl‐2 and Bcl‐x were downregulated. LukS‐PV can induce apoptosis in AML cells by targeting C5aR. C5aR may be a potential therapeutic target for AML and LukS‐PV is a candidate targeted drug for the treatment of AML.