Timosaponin AIII is preferentially cytotoxic to tumor cells through inhibition of mTOR and induction of ER stress.
Timosaponin AIII is preferentially cytotoxic to tumor cells through inhibition of mTOR and induction of ER stress.
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DOI：
10.1371/journal.pone.0007283
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发表时间：
2009-09-30
期刊：
影响因子：
3.7
通讯作者：
Shtivelman E
中科院分区：
文献类型：
--
作者：
King FW;Fong S;Griffin C;Shoemaker M;Staub R;Zhang YL;Cohen I;Shtivelman E
知母的水提取物（BN 108）在各种癌细胞系中诱导细胞凋亡，但在非转化细胞中的细胞毒性显著降低。BN 108的化学分级显示其细胞毒性与知母皂苷、粪甾烷型甾体皂苷有关。知母皂苷BII（TBII）是BN 108中的主要皂苷，但其显示出很小的细胞毒性。丰度低得多的TAIII在肿瘤细胞中诱导细胞死亡，但在正常细胞中不诱导细胞死亡，再现了总提取物BN 108的选择性。糖苷酶处理通过去除TBII中的额外糖部分，将其转化为TAIII并赋予细胞毒性活性。对TAIII诱导的死亡机制的分析揭示了两种不同的促凋亡途径的激活：第一，mTORC 1的抑制表现为mTORC 1靶点的磷酸化大大减少;第二，诱导内质网应激，最终导致eIF 2 α的磷酸化和caspase 4的激活。这些促凋亡途径在肿瘤细胞中被TAIII选择性激活，但在正常细胞中不被激活。这两种途径在TAIII细胞毒性中起着致病作用，因为单独恢复mTOR活性或缓解ER应激仅提供对TAIII的部分保护。抑制mTORC 1和诱导ER应激显然有助于诱导先前报道的TAIII处理的细胞中的自噬反应。TAIII诱导的自噬在TAIII诱导的死亡信号传导中起保护作用，并且未能启动自噬应答与对TAIII诱导的细胞凋亡的敏感性增加相关。对TAIII的多种死亡促进和明显的肿瘤选择性反应，其抑制mTORC 1的能力，以及通过药理学抑制自噬进一步增强其细胞毒性的可能性，使TAIII成为开发为癌症治疗剂的有吸引力的候选者。
The aqueous extract of Anemarrhena asphodeloides (BN108) induces apoptosis in various cancer cell lines but is significantly less cytotoxic in non-transformed cells. Chemical fractionation of BN108 showed that its cytotoxicity is associated with timosaponins, steroidal saponins of coprostane type. Timosaponin BII (TBII) is a major saponin in BN108, but it shows little cytotoxicity. A much less abundant TAIII induces cell death in tumor cells but not in normal cells, reproducing the selectivity of the total extract BN108. Glycosidase treatment, by removing the extra sugar moiety in TBII, converts it to TAIII and confers cytotoxic activity. Analysis of the mechanisms of death induced by TAIII revealed activation of two distinct pro-apoptotic pathways: first, inhibition of mTORC1 manifested in much reduced phosphorylation of mTORC1 targets; second, induction of endoplasmic reticulum stress culminating in phosphorylation of eIF2α and activation of caspase 4. These pro-apoptotic pathways are activated by TAIII selectively in tumor cells but not in normal cells. Both pathways play a causative role in TAIII cytotoxicity, as restoration of either mTOR activity or relief of ER stress alone offer only partial protection from TAIII. Inhibition of mTORC1 and induction of ER stress apparently contribute to the induction of the previously reported autophagic response in TAIII-treated cells. TAIII induced autophagy plays a protective role in TAIII induced death signaling, and failure to mount autophagic response is associated with heightened sensitivity to TAIII induced apoptosis. The multiple death-promoting and apparently tumor-selective responses to TAIII, its ability to inhibit mTORC1, and the possibility of further enhancing its cytotoxicity by pharmacological inhibition of autophagy, make TAIII an attractive candidate for development as a cancer therapeutic agent.
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影响因子：
7.8
作者：
Hitomi, Junichi;Katayama, Taiichi;Eguchi, Yutaka;Kudo, Takashi;Taniguchi, Manabu;Koyama, Yoshihisa;Manabe, Takayuki;Yamagishi, Satoru;Bando, Yoshio;Imaizumi, Kazunori;Tsujimoto, Yoshihide;Tohyama, Masaya
通讯作者：
Tohyama, Masaya
影响因子：
9.8
作者：
Feldman ME;Apsel B;Uotila A;Loewith R;Knight ZA;Ruggero D;Shokat KM
通讯作者：
Shokat KM
影响因子：
16
作者：
Ellisen, LW;Ramsayer, KD;Haber, DA
通讯作者：
Haber, DA
影响因子：
21.3
作者：
Jacinto, E;Loewith, R;Hall, MN
通讯作者：
Hall, MN
影响因子：
10.5
作者：
Brugarolas, J;Lei, K;Kaelin, WG
通讯作者：
Kaelin, WG