title: Cross-talk of alpha tocopherol-associated protein and JNK controls the oxidative stress-induced apoptosis in prostate cancer cells.
abstract: Excess intracellular reactive oxygen species (ROS) beyond a threshold can induce apoptosis in cancer cells. However, the signal pathways that can augment the proapoptotic function of ROS remain largely unknown. We previously identified a tumor suppressor, alpha-tocopherol-associated protein (TAP), yet little is known regarding the role of TAP in the apoptotic signaling in prostate cancer. Interestingly, we recently found that exposure of prostate cancer cells to hydrogen peroxide (H(2)O(2) ) resulted in induced apoptosis as well as increased expression of TAP. Small interfering RNA (siRNA) mediated silencing of endogenous TAP expression conferred effective protection from H(2)O(2) -induced apoptosis. Further mechanistic study showed exposure of prostate cancer cells to H(2)O(2) resulted in increased phosphorylation of both JNK and c-Jun, and TAP siRNA effectively decreased H(2)O(2) -induced JNK and c-Jun phosphorylation. Immunoprecipitation experiments revealed that JNK physically associates with TAP. Furthermore, signaling downstream of JNK to the AP-1 complex and BH-3-only subfamily were found to be regulated on changing the TAP expression status. TAP could also promote the oxidative stress-induced apoptosis effect of docetaxel. In the mice xenograft model, H(2)O(2) treatment induced TAP expression, JNK phosphorylation and apoptosis of prostate cancer. Recombinant adeno-associated virus 2 (rAAV2)-TAP injection significantly sensitizes this H(2)O(2) proapoptotic effect. Together, we have identified a novel functional mechanism that the cross-talk of TAP-JNK is involved in oxidative stress-induced apoptosis in prostate cancer cells. Disrupting the redox balance of cancer cells by this signaling may enable therapeutic selectivity and provide benefit to overcome the drug resistance of prostate cancer.
authors.affiliation: Department of Urology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou 510630, China.
authors.forename: Baoyi
authors.initials: B
authors.lastname: Zhu
authors.forename: Xiaojuan
authors.initials: X
authors.lastname: Li
authors.forename: Yuying
authors.initials: Y
authors.lastname: Zhang
authors.forename: Chunwei
authors.initials: C
authors.lastname: Ye
authors.forename: Yu
authors.initials: Y
authors.lastname: Wang
authors.forename: Songwang
authors.initials: S
authors.lastname: Cai
authors.forename: Huaiqiu
authors.initials: H
authors.lastname: Huang
authors.forename: Yi
authors.initials: Y
authors.lastname: Cai
authors.forename: Shuyuan
authors.initials: S
authors.lastname: Yeh
authors.forename: Zhenhua
authors.initials: Z
authors.lastname: Huang
authors.forename: Ruihan
authors.initials: R
authors.lastname: Chen
authors.forename: Yiran
authors.initials: Y
authors.lastname: Tao
authors.forename: Xingqiao
authors.initials: X
authors.lastname: Wen
mesh_terms: D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation; D020868:Gene Silencing; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D047468:Immunoprecipitation; D020287:In Situ Nick-End Labeling; D048670:MAP Kinase Kinase 4 / Q000378:metabolism*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D018384:Oxidative Stress; D016133:Polymerase Chain Reaction / Q000379:methods; D011471:Prostatic Neoplasms / Q000201:enzymology / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D020239:Receptor Cross-Talk; D015398:Signal Transduction; D014183:Transplantation, Heterologous
chemical_list: D002352:Carrier Proteins; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; C017763:alpha-tocopherol transfer protein; D006861:Hydrogen Peroxide; D048670:MAP Kinase Kinase 4