title: Inhibition of AKT/FoxO3a signaling induced PUMA expression in response to p53-independent cytotoxic effects of H1: A derivative of tetrandrine.
abstract: PUMA (p53 unregulated modulator of apoptosis), a BH3-only Bcl-2 family member, can be induced by p53-dependent and p53-independent manners. It plays an important role as regulator of cellular apoptosis. Herein, we evaluate the effects of H1 (a derivative of tetrandrine) on induction of PUMA and underlie its potential mechanism in p53-independent cytotoxic response. Anti-proliferative activity and evidently cytotoxic activity of H1 were observed in wild-type and p53 null cells. Further studies demonstrated that H1 resulted in an increase of cleaved PARP, decease of survivin and elevation of p-H2AX. What is more, H1 significantly induced PUMA expression in a concentration- and time-dependent manner and caused an increase of Bax/Bcl-2 ratio in p53 null cells. Of note, knockdown of PUMA attenuated cytotoxic activity of H1. Further studies demonstrated that inhibition of AKT/FoxO3a signaling contributed to H1-mediated PUMA induction. Targeted suppression of AKT/FoxO3a signaling by siRNA could overcome H1-mediated PUMA induction. In addition, H1 significantly suppressed NF-κB activity and caused an increase of early apoptotic and late apoptotic cells, and elevated caspase-3 activity. Taken together, we found that inhibition of AKT/FoxO3a signaling may contribute to H1-mediated PUMA induction, suggesting that inhibition of AKT/FoxO3a signaling result in PUMA expression in response to p53-independent cytotoxic effects of H1.
authors.affiliation: a Liaoning Medical University; Jinzhou , PR China.
authors.forename: Yin-Xu
authors.initials: YX
authors.lastname: Zhang
authors.forename: Xiao-Mei
authors.initials: XM
authors.lastname: Liu
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.forename: Jun
authors.initials: J
authors.lastname: Li
authors.forename: Ying
authors.initials: Y
authors.lastname: Liu
authors.forename: Hua
authors.initials: H
authors.lastname: Zhang
authors.forename: Xue-Wen
authors.initials: XW
authors.lastname: Yu
authors.forename: Ning
authors.initials: N
authors.lastname: Wei
mesh_terms: D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000235:genetics*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival / Q000187:drug effects; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D055786:Gene Knockout Techniques; D006657:Histones / Q000378:metabolism*; D006801:Humans; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D051017:Apoptosis Regulatory Proteins; C438378:BBC3 protein, human; C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D006657:Histones; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53; D051057:Proto-Oncogene Proteins c-akt
keywords: AKT/FoxO3a signaling; FoxO3a, Forkhead Homeobox type O3a; NF-κB, Nuclear Factor Kappa-light-chain-enhancer of activated B cells; PARP, Poly ADP (Adenosine Diphosphate)-Ribose Polymerase; PUMA, p53 Unregulated Modulator of Apoptosis; Tet, Tetrandrine; TNF-α, Tumor Necrosis Fa; PUMA; apoptosis; cytotoxicity; p53; tetrandrine