Cholesterol-enriched membrane micro-domaindeficiency induces doxorubicin resistancevia promoting autophagy in breast cancer.
Cholesterol-enriched membrane micro-domaindeficiency induces doxorubicin resistancevia promoting autophagy in breast cancer.
复制标题
DOI：
10.1016/j.omto.2021.10.005
复制
发表时间：
2021-12-17
期刊：
影响因子：
--
通讯作者：
Shen HM
中科院分区：
文献类型：
--
作者：
Shi Y;Ye Z;Lu G;Yang N;Zhang J;Wang L;Cui J;Del Pozo MA;Wu Y;Xia D;Shen HM
耐药性已成为癌症化疗的最大挑战之一。在某些条件下，癌细胞劫持自噬以科普治疗压力，这在很大程度上破坏了化疗的疗效。目前，指示自噬衍生的耐药性的生物标志物在很大程度上仍然具有包容性。在这里，我们报告了一个新的作用，脂筏/胆固醇富集膜微域（CEMMs）在自噬体生物合成和阿霉素耐药的乳腺肿瘤。我们发现，CEMM是VAMP 3与突触融合蛋白6（STX 6，胆固醇结合SNARE蛋白）相互作用所必需的。在CEMM破坏后，VAMP 3从STX 6释放，导致含有ATG 16 L1的囊泡运输到再循环内体和随后的自噬体生物发生。此外，我们发现乳腺癌患者的CEMM标志物CAV 1降低，并且CEMM缺陷诱导的自噬与多柔比星抗性相关，自噬抑制可克服多柔比星抗性。综上所述，我们提出了一种新的模型，即在回收内体中的CEMM支持VAMP 3和STX 6的相互作用，并作为屏障限制VAMP 3在自噬囊泡融合中的活性，因此CEMM缺陷促进乳腺肿瘤中的自噬体生物发生和多柔比星抗性。
Drug resistance has become one of the largest challenges for cancer chemotherapies. Under certain conditions, cancer cells hijack autophagy to cope with therapeutic stress, which largely undermines the chemo-therapeutic efficacy. Currently, biomarkers indicative of autophagy-derived drug resistance remain largely inclusive. Here, we report a novel role of lipid rafts/cholesterol-enriched membrane micro-domains (CEMMs) in autophagosome biogenesis and doxorubicin resistance in breast tumors. We showed that CEMMs are required for the interaction of VAMP3 with syntaxin 6 (STX6, a cholesterol-binding SNARE protein). Upon disruption of CEMM, VAMP3 is released from STX6, resulting in the trafficking of ATG16L1-containing vesicles to recycling endosomes and subsequent autophagosome biogenesis. Furthermore, we found that CEMM marker CAV1 is decreased in breast cancer patients and that the CEMM deficiency-induced autophagy is related to doxorubicin resistance, which is overcome by autophagy inhibition. Taken together, we propose a novel model whereby CEMMs in recycling endosomes support the VAMP3 and STX6 interaction and function as barriers to limit the activity of VAMP3 in autophagic vesicle fusion, thus CEMM deficiency promotes autophagosome biogenesis and doxorubicin resistance in breast tumors.
登录
查看更多内容
影响因子：
64.8
作者：
Diao, Jiajie;Liu, Rong;Rong, Yueguang;Zhao, Minglei;Zhang, Jing;Lai, Ying;Zhou, Qiangjun;Wilz, Livia M.;Li, Jianxu;Vivona, Sandro;Pfuetzner, Richard A.;Brunger, Axel T.;Zhong, Qing
通讯作者：
Zhong, Qing
DOI：
10.1523/jneurosci.2337-12.2013
发表时间：
2013-03-27
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Degtyar V;Hafez IM;Bray C;Zucker RS
通讯作者：
Zucker RS
影响因子：
2.7
作者：
Guan J;Yuan Z;He J;Wu Z;Liu B;Lin X;Mo L;Mo H
通讯作者：
Mo H
DOI：
10.1007/978-3-030-14265-0_1
发表时间：
2019-01-01
期刊：
DIRECT MECHANISMS IN CHOLESTEROL MODULATION OF PROTEIN FUNCTION
影响因子：
--
作者：
Fantini, Jacques;Epand, Richard M.;Barrantes, Francisco J.
通讯作者：
Barrantes, Francisco J.
影响因子：
11.4
作者：
Fraldi, Alessandro;Annunziata, Fabio;Ballabio, Andrea
通讯作者：
Ballabio, Andrea