Highly expressed SERCA2 triggers tumor cell autophagy and is a druggable vulnerability in triple-negative breast cancer.
Highly expressed SERCA2 triggers tumor cell autophagy and is a druggable vulnerability in triple-negative breast cancer.
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DOI：
10.1016/j.apsb.2022.05.009
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发表时间：
2022-12
影响因子：
14.5
通讯作者：
Xu, Qiang
中科院分区：
文献类型：
--
作者：
Fan, Minmin;Gao, Jian;Zhou, Lin;Xue, Wenwen;Wang, Yixuan;Chen, Jingwei;Li, Wuhao;Yu, Ying;Liu, Bo;Shen, Yan;Xu, Qiang
化疗耐药仍然是成功治疗三阴性乳腺癌（TNBC）的主要障碍。识别可用药脆弱性是TNBC治疗的重要目标。在这里，我们报道了SERCA2表达与人类患者TNBC的进展相关，这促进了TNBC细胞的增殖、迁移和化疗耐药。机制上，SERCA2通过LIR基序与LC3B相互作用，促进wipi2独立自噬体的形成，诱导自噬。自噬介导的SERCA2降解通过Ca2+/CaMKK/CREB-1反馈诱导SERCA2转激活。此外，我们发现serca2靶向小分子RL71增强SERCA2-LC3B相互作用，诱导过度自噬细胞死亡。在体外和体内，SERCA2表达的增加使TNBC细胞倾向于rl71诱导的自噬细胞死亡。本研究阐明了TNBC细胞维持其高自噬活性诱导化疗耐药的机制，并提示SERCA2表达升高是TNBC的可药物易感性。SERCA2表达增加可增强自噬活性，诱导化疗耐药，可能是TNBC治疗的可药物易感性。
Chemoresistance remains a major obstacle to successful treatment of triple negative breast cancer (TNBC). Identification of druggable vulnerabilities is an important aim for TNBC therapy. Here, we report that SERCA2 expression correlates with TNBC progression in human patients, which promotes TNBC cell proliferation, migration and chemoresistance. Mechanistically, SERCA2 interacts with LC3B via LIR motif, facilitating WIPI2-independent autophagosome formation to induce autophagy. Autophagy-mediated SERCA2 degradation induces SERCA2 transactivation through a Ca2+/CaMKK/CREB-1 feedback. Moreover, we found that SERCA2-targeting small molecule RL71 enhances SERCA2–LC3B interaction and induces excessive autophagic cell death. The increase in SERCA2 expression predisposes TNBC cells to RL71-induced autophagic cell death in vitro and in vivo. This study elucidates a mechanism by which TNBC cells maintain their high autophagy activity to induce chemoresistance, and suggests increased SERCA2 expression as a druggable vulnerability for TNBC. Increased SERCA2 expression enhances autophagy activity to induce chemoresistance, and might be a druggable vulnerability for TNBC therapy.
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影响因子：
11.2
作者：
Maycotte P;Gearheart CM;Barnard R;Aryal S;Mulcahy Levy JM;Fosmire SP;Hansen RJ;Morgan MJ;Porter CC;Gustafson DL;Thorburn A
通讯作者：
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影响因子：
5.6
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通讯作者：
Tschan MP
影响因子：
16
作者：
Ganley IG;Wong PM;Gammoh N;Jiang X
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Jiang X
影响因子：
12.4
作者：
Dasari SK;Bialik S;Levin-Zaidman S;Levin-Salomon V;Merrill AH Jr;Futerman AH;Kimchi A
通讯作者：
Kimchi A
影响因子：
10.5
作者：
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通讯作者：
White, Eileen