Adipocyte-Derived Exosomal MTTP Suppresses Ferroptosis and Promotes Chemoresistance in Colorectal Cancer.
Adipocyte-Derived Exosomal MTTP Suppresses Ferroptosis and Promotes Chemoresistance in Colorectal Cancer.
复制标题
DOI：
10.1002/advs.202203357
复制
发表时间：
2022-10
期刊：
影响因子：
15.1
通讯作者：
Ba, Yi
中科院分区：
文献类型：
--
作者：
Zhang, Qiumo;Deng, Ting;Zhang, Hongdian;Zuo, Duo;Zhu, Qihang;Bai, Ming;Liu, Rui;Ning, Tao;Zhang, Le;Yu, Zhentao;Zhang, Haiyang;Ba, Yi
肥胖与晚期结直肠癌(CRC)患者预后不良密切相关，但其机制尚不清楚。铁下垂是一种非凋亡性细胞死亡，其特征是脂质活性氧簇(ROS)积聚和铁依赖，并与肿瘤的化疗耐药有关。在这里，研究表明，脂肪来源的外切体降低了结直肠癌对铁性下垂的易感性，从而促进了对奥沙利铂的化疗耐药性。研究发现，高体脂比例的结直肠癌患者血浆外切体中微粒体甘油三酯转运蛋白(MTTP)的表达增加，作为铁下垂的抑制因子，降低了对化疗的敏感性。在机制上，MTTP/富含脯氨酸的酸性蛋白1(PRAP1)复合体抑制锌指E盒结合同源异型盒1的表达，上调谷胱甘肽过氧化物酶4和XCT，导致多不饱和脂肪酸比例和脂质ROS水平下降。此外，在有机化合物中进行了实验，并建立了肥胖小鼠的肿瘤移植模型，证明抑制MTTP增加了对化疗的敏感性。这些结果揭示了一种由脂肪来源的外切体介导的新的细胞内信号通路，并提示针对分泌的MTTP的治疗可能逆转结直肠癌对奥沙利铂的耐药性。作者表明，脂肪来源的外切体降低了结直肠癌对铁性下垂的易感性，从而促进了对奥沙利铂的化疗耐药性。高体脂比例的结直肠癌患者血浆外切体中MTTP的表达增加，导致多不饱和脂肪酸(PUFA)比例和脂质ROS水平降低，从而抑制铁下垂，降低对化疗的敏感性。
Obesity is closely related to a poor prognosis in patients with advanced colorectal cancer (CRC), but the mechanisms remain unclear. Ferroptosis is a form of nonapoptotic cell death characterized by lipid reactive oxygen species (ROS) accumulation and iron dependency and is associated with the chemoresistance of tumors. Here, it is shown that adipose‐derived exosomes reduce ferroptosis susceptibility in CRC, thus promoting chemoresistance to oxaliplatin. It is found that microsomal triglyceride transfer protein (MTTP) expression is increased in the plasma exosomes of CRC patients with a high body fat ratio, serving as an inhibitor of ferroptosis and reducing sensitivity to chemotherapy. Mechanistically, the MTTP/proline‐rich acidic protein 1 (PRAP1) complex inhibited zinc finger E‐box binding homeobox 1 expression and upregulated glutathione peroxidase 4 and xCT, leading to a decreased polyunsaturated fatty acids ratio and lipid ROS levels. Moreover, experiments are carried out in organoids, and a tumor implantation model is established in obese mice, demonstrating that the inhibition of MTTP increases the sensitivity to chemotherapy. The results reveal a novel intracellular signaling pathway mediated by adipose‐derived exosomes and suggest that treatments targeting secreted MTTP might reverse oxaliplatin resistance in CRC. The authors show that adipose‐derived exosomes reduce ferroptosis susceptibility in CRC, thus promoting chemoresistance to oxaliplatin. MTTP expression is increased in the plasma exosomes of CRC patients with a high body fat ratio, leading to a decreased polyunsaturated fatty acid (PUFA) ratio and lipid ROS levels, which serving as an inhibitor of ferroptosis and reducing sensitivity to chemotherapy.
登录
查看更多内容
ACSL4 通过塑造细胞脂质成分来决定铁死亡敏感性。
影响因子：
14.8
作者：
Doll S;Proneth B;Tyurina YY;Panzilius E;Kobayashi S;Ingold I;Irmler M;Beckers J;Aichler M;Walch A;Prokisch H;Trümbach D;Mao G;Qu F;Bayir H;Füllekrug J;Scheel CH;Wurst W;Schick JA;Kagan VE;Angeli JP;Conrad M
通讯作者：
Conrad M
影响因子：
14.8
作者：
Kagan VE;Mao G;Qu F;Angeli JP;Doll S;Croix CS;Dar HH;Liu B;Tyurin VA;Ritov VB;Kapralov AA;Amoscato AA;Jiang J;Anthonymuthu T;Mohammadyani D;Yang Q;Proneth B;Klein-Seetharaman J;Watkins S;Bahar I;Greenberger J;Mallampalli RK;Stockwell BR;Tyurina YY;Conrad M;Bayır H
通讯作者：
Bayır H
影响因子：
64.5
作者：
Dixon SJ;Lemberg KM;Lamprecht MR;Skouta R;Zaitsev EM;Gleason CE;Patel DN;Bauer AJ;Cantley AM;Yang WS;Morrison B 3rd;Stockwell BR
通讯作者：
Stockwell BR
DOI：
10.1126/science.aaw9872
发表时间：
2020-04-03
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Badgley MA;Kremer DM;Maurer HC;DelGiorno KE;Lee HJ;Purohit V;Sagalovskiy IR;Ma A;Kapilian J;Firl CEM;Decker AR;Sastra SA;Palermo CF;Andrade LR;Sajjakulnukit P;Zhang L;Tolstyka ZP;Hirschhorn T;Lamb C;Liu T;Gu W;Seeley ES;Stone E;Georgiou G;Manor U;Iuga A;Wahl GM;Stockwell BR;Lyssiotis CA;Olive KP
通讯作者：
Olive KP
影响因子：
45.3
作者：
Kitahara, Cari M.;Berndt, Sonja I.;Huang, Wen-Yi
通讯作者：
Huang, Wen-Yi