title: DNA damage and ER stress contribute to oblongifolin C-induced cell killing in Bax/Bak-deficient cells.
abstract: A key clinical problem in oncology is the treatment of apoptosis-resistant tumors. Tumor cells deficient in both of the proapoptotic proteins Bax and Bak are protected against most chemotherapeutic drug-induced apoptosis. We report here that a natural compound, oblongifolin C (OC), effectively eliminates Bax/Bak-deficient murine embryonic fibroblasts and colon carcinoma HCT116 cells. OC not only triggers DNA double-strand breaks and DNA damage response, but also inhibits repair of DNA damage. In addition, OC induces ER stress through upregulation of the transcription factor CHOP and activation of JNK kinases. Upon treatment with OC, cells undergo Bax/Bak-independent, caspase-mediated apoptosis. Taken together, our data establish a rationale for the broad use of OC to treat apoptosis deficient tumors.
authors.affiliation: School of Life Sciences, Tsinghua University, Beijing 100084, China; Key Lab in Healthy Science and Technology, Division of Life Science, Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Xu
authors.affiliation: School of Life Sciences, Tsinghua University, Beijing 100084, China; Key Lab in Healthy Science and Technology, Division of Life Science, Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, China.
authors.forename: Min
authors.initials: M
authors.lastname: Cheng
authors.affiliation: School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
authors.forename: Yuanzhi
authors.initials: Y
authors.lastname: Lao
authors.affiliation: School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Wang
authors.affiliation: School of Life Sciences, Tsinghua University, Beijing 100084, China; Key Lab in Healthy Science and Technology, Division of Life Science, Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, China.
authors.forename: Jiangbin
authors.initials: J
authors.lastname: Wu
authors.affiliation: Department of Endocrinology and Metabolism, Peking University People's Hospital, Beijing 100044, China.
authors.forename: Lingli
authors.initials: L
authors.lastname: Zhou
authors.affiliation: Key Lab in Healthy Science and Technology, Division of Life Science, Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, China.
authors.forename: Yaou
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China. Electronic address: xuhongxi88@gmail.com.
authors.forename: Hongxi
authors.initials: H
authors.lastname: Xu
authors.affiliation: Key Lab in Healthy Science and Technology, Division of Life Science, Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, China. Electronic address: xu.naihan@sz.tsinghua.edu.cn.
authors.forename: Naihan
authors.initials: N
authors.lastname: Xu
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology*; D020169:Caspases / Q000378:metabolism; D002478:Cells, Cultured; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D053903:DNA Breaks, Double-Stranded; D004249:DNA Damage; D004260:DNA Repair / Q000187:drug effects; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D045325:HCT116 Cells; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D013729:Terpenes / Q000494:pharmacology*; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000172:deficiency* / Q000235:genetics; D051028:bcl-2-Associated X Protein / Q000172:deficiency* / Q000235:genetics
chemical_list: D000972:Antineoplastic Agents, Phytogenic; C494773:Bak1 protein, mouse; C494827:Bax protein, mouse; D013729:Terpenes; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; C575447:oblongifolin C; D020169:Caspases
keywords: Apoptosis; BAK; BAX; DNA damage; ER stress; Oblongifolin C