Oleanolic acid blocks the purine salvage pathway for cancer therapy by inactivating SOD1 and stimulating lysosomal proteolysis.
Oleanolic acid blocks the purine salvage pathway for cancer therapy by inactivating SOD1 and stimulating lysosomal proteolysis.
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齐墩果酸通过灭活 SOD1 和刺激溶酶体蛋白水解来阻断癌症治疗的嘌呤补救途径
DOI：
10.1016/j.omto.2021.08.013
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发表时间：
2021-12-17
期刊：
影响因子：
--
通讯作者：
Chen WL
中科院分区：
文献类型：
--
作者：
Liu D;Jin X;Yu G;Wang M;Liu L;Zhang W;Wu J;Wang F;Yang J;Luo Q;Cai L;Yang X;Ke X;Qu Y;Xu Z;Jia L;Chen WL
代谢重编程是癌症的核心标志，是肿瘤发生和肿瘤进展的关键。通过研究抗癌化合物的代谢扰动，可以深入了解这些药物的潜在机制，并确定新的抗癌靶点。在这里，我们证明了油酸（OA）的管理迅速改变癌症代谢，特别是抑制嘌呤补救途径（PSP）。PSP恢复显着反对OA诱导的DNA复制和细胞增殖停滞，强调了这一途径的重要性，OA的抗癌活性。次黄嘌呤-鸟嘌呤磷酸核糖转移酶（HGPRT）和5′-核苷酸酶（5′-NT）是PSP活性所必需的两种代谢酶，OA通过溶酶体途径迅速降解它们。OA选择性地靶向超氧化物歧化酶1（SOD 1），产生活性氧（ROS），激活AMP活化蛋白激酶（AMPK）/哺乳动物雷帕霉素靶蛋白复合物1（mTORC 1）/巨自噬通路，从而引起HGPRT和5′-NT的溶酶体降解。此外，我们发现PSP在人类肺癌和乳腺癌中过度激活，与患者生存率呈负相关。本研究结果阐明了OA通过SOD 1/ROS/AMPK/mTORC 1/巨自噬/溶酶体途径抑制PSP的新的抗癌机制。我们还确定了PSP作为癌症治疗的新靶点，并强调OA作为具有高PSP活性的癌症的潜在治疗剂。对具有抗癌活性的天然化合物的机理研究将为癌症治疗确定新的靶点。我们发现嘌呤补救途径（PSP）是油酸（OA）治疗癌症的重要靶点。OA通过激活SOD 1/ROS/AMPK/mTORC 1/macroautophagy/lysosomal pathway抑制肿瘤细胞的PSP。
Metabolic reprogramming is a core hallmark of cancer and is key for tumorigenesis and tumor progression. Investigation of metabolic perturbation by anti-cancer compounds would allow a thorough understanding of the underlying mechanisms of these agents and identification of new anti-cancer targets. Here, we demonstrated that the administration of oleanolic acid (OA) rapidly altered cancer metabolism, particularly suppressing the purine salvage pathway (PSP). PSP restoration significantly opposed OA-induced DNA replication and cell proliferation arrest, underscoring the importance of this pathway for the anti-cancer activity of OA. Hypoxanthine-guanine phosphoribosyltransferase (HGPRT) and 5′-nucleotidase (5′-NT), two metabolic enzymes essential for PSP activity, were promptly degraded by OA via the lysosome pathway. Mechanistically, OA selectively targeted superoxide dismutase 1 (SOD1) and yielded reactive oxygen species (ROS) to activate the AMP-activated protein kinase (AMPK)/mammalian target of rapamycin complex 1 (mTORC1)/macroautophagy pathway, thus eliciting lysosomal degradation of HGPRT and 5′-NT. Furthermore, we found that the PSP was overactivated in human lung and breast cancers, with a negative correlation with patient survival. The results of this study elucidated a new anti-cancer mechanism of OA by restraining the PSP via the SOD1/ROS/AMPK/mTORC1/macroautophagy/lysosomal pathway. We also identified the PSP as a new target for cancer treatment and highlighted OA as a potential therapeutic agent for cancers with high PSP activity. Mechanistic study of natural compounds with anti-cancer activity would identify new targets for cancer treatment. Here we found that the purine salvage pathway (PSP) was a crucial target of oleanolic acid (OA) for cancer therapy. Moreover, OA suppressed PSP of cancer cells via activating the SOD1/ROS/AMPK/mTORC1/macroautophagy/lysosomal pathway.
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影响因子：
5.8
作者：
Martin KR;Celano SL;Solitro AR;Gunaydin H;Scott M;O'Hagan RC;Shumway SD;Fuller P;MacKeigan JP
通讯作者：
MacKeigan JP
影响因子：
3.3
作者：
Liou GY;Storz P
通讯作者：
Storz P
影响因子：
20.3
作者：
Chen, Wen-Lian;Wang, Jing-Han;Jia, Wei
通讯作者：
Jia, Wei
影响因子：
64.5
作者：
Faubert B;Li KY;Cai L;Hensley CT;Kim J;Zacharias LG;Yang C;Do QN;Doucette S;Burguete D;Li H;Huet G;Yuan Q;Wigal T;Butt Y;Ni M;Torrealba J;Oliver D;Lenkinski RE;Malloy CR;Wachsmann JW;Young JD;Kernstine K;DeBerardinis RJ
通讯作者：
DeBerardinis RJ
影响因子：
29
作者：
Hardie DG
通讯作者：
Hardie DG