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KMID : 0545120170270010197
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Journal of Microbiology and Biotechnology
2017 Volume.27 No. 1 p.197 ~ p.205
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Pharmacologic Inhibition of Autophagy Sensitizes Human Acute Leukemia Jurkat T Cells to Acacetin-Induced Apoptosis
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Lee Ji-Young
Jun Do-Youn
Kim Ki-Yun
Ha Eun-Ji
Woo Mi-Hee
Ko Jee-Youn
Yun Young-Ho
Oh In-Seok
Kim Young-Ho
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Abstract
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Exposure of Jurkat T cell clone (J/Neo cells) to acacetin (5,7-dihydroxy-4’-methoxyflavone), which is present in barnyard millet (Echinochloa esculenta (A. Braun)) grains, caused cytotoxicity, enhancement of apoptotic sub-G1 rate, Bak activation, loss of mitochondrial membrane potential (Δψm), activation of caspase-9 and caspase-3, degradation of poly(ADPribose) polymerase, and FITC-Annexin V-stainable phosphatidylserine exposure on the external surface of the cytoplasmic membrane without accompanying necrosis. These apoptotic responses were abrogated in Jurkat T cell clone (J/Bcl-xL) overexpressing Bcl-xL. Under the same conditions, cellular autophagic responses, including suppression of the AktmTOR pathway and p62/SQSTM1 down-regulation, were commonly detected in J/Neo and J/Bcl-xL cells; however, formation of acridine orange-stainable acidic vascular organelles, LC3-I/II conversion, and Beclin-1 phosphorylation (Ser-15) were detected only in J/Neo cells. Correspondingly, concomitant treatment with the autophagy inhibitor (3-methyladenine or LY294002) appeared to enhance acacetin-induced apoptotic responses, such as Bak activation, Δψm loss, activation of caspase-9 and caspase-3, and apoptotic sub-G1 accumulation. This indicated that acacetin could induce apoptosis and cytoprotective autophagy in Jurkat T cells simultaneously. Together, these results demonstrate that acacetin induces not only apoptotic cell death via activation of Bak, loss of Δψm, and activation of the mitochondrial caspase cascade, but also cytoprotective autophagy resulting from suppression of the Akt-mTOR pathway. Furthermore, pharmacologic inhibition of the autophagy pathway augments the activation of Bak and resultant mitochondrial damage-mediated apoptosis in Jurkat T cells.
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KEYWORD
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Acacetin, Bak activation, cytoprotective autophagy, Echinochloa esculenta (A. Braun), Jurkat T cells, mitochondria-dependent apoptosis
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