Targeting SPHK1/S1PR3-regulated S-1-P metabolic disorder triggers autophagic cell death in pulmonary lymphangiomyomatosis (LAM).
Targeting SPHK1/S1PR3-regulated S-1-P metabolic disorder triggers autophagic cell death in pulmonary lymphangiomyomatosis (LAM).
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靶向 SPHK1/S1PR3 调节的 S-1-P 代谢紊乱可触发肺淋巴管肌瘤病 (LAM) 中的自噬细胞死亡
DOI：
10.1038/s41419-022-05511-3
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发表时间：
2022-12-21
影响因子：
9
通讯作者：
Li, Chenggang
中科院分区：
文献类型：
--
作者：
Li, Fei;Zhang, Yifan;Lin, Zhoujun;Yan, Lizhong;Liu, Qiao;Li, Yin;Pei, Xiaolin;Feng, Ya;Han, Xiao;Yang, Juan;Zheng, Fangxu;Li, Tianjiao;Zhang, Yupeng;Fu, Zhenkun;Shao, Di;Yu, Jane;Li, Chenggang
淋巴管平滑肌瘤病（LAM）是一种进行性肺部疾病，只影响女性，是由编码基因结节性硬化症复合物1（TSC 1）或TSC 2的缺陷或突变引起的，导致哺乳动物雷帕霉素复合物1（mTORC 1）激活和自噬抑制。临床上，雷帕霉素显示有限的杀细胞作用，并且LAM在停药后复发。在这项研究中，我们证明，TSC 2负调节鞘脂代谢途径和鞘氨醇激酶1（SPHK 1）和鞘氨醇-1-磷酸受体3（S1 PR 3）的表达显着升高LAM患者来源的TSC 2缺陷细胞相比，TSC 2 addback细胞，不敏感雷帕霉素治疗和雌激素刺激。SPHK 1的敲除显示TSC 2缺陷细胞的活力、迁移和侵袭降低。选择性SPHK 1拮抗剂PF 543有效抑制TSC 2缺陷细胞的活力并诱导自噬介导的细胞死亡。同时，同源受体S1 PR 3被鉴定为介导1-磷酸鞘氨醇（S1 P）的致瘤作用。用TY 52156（S1 PR 3的选择性拮抗剂）处理或使用S1 PR 3-siRNA进行基因沉默可以抑制TSC 2缺陷细胞的活力。SPHK 1和S1 PR 3抑制剂在TSC 2缺失细胞的异种移植模型中均显著表现出抗肿瘤作用，恢复自噬水平，并触发细胞死亡。总之，我们确定了新的雷帕霉素不敏感的神经鞘氨醇代谢签名在TSC 2无效LAM细胞。异常SPHK 1/S1 P/S1 PR 3信号传导的治疗靶向可能对具有自噬抑制的TSC/LAM或其他过度活跃的mTOR肿瘤的患者具有有效的治疗益处。
Lymphangioleiomyomatosis (LAM), a progressive pulmonary disease exclusively affecting females, is caused by defects or mutations in the coding gene tuberous sclerosis complex 1 (TSC1) or TSC2, causing the mammalian target of rapamycin complex 1 (mTORC1) activation and autophagy inhibition. Clinically, rapamycin shows limited cytocidal effects, and LAM recurs after drug withdrawal. In this study, we demonstrated that TSC2 negatively regulated the sphingolipid metabolism pathway and the expressions of sphingosine kinase 1 (SPHK1) and sphingosine-1-phosphate receptor 3 (S1PR3) were significantly elevated in LAM patient-derived TSC2-deficient cells compared to TSC2-addback cells, insensitive to rapamycin treatment and estrogen stimulation. Knockdown of SPHK1 showed reduced viability, migration and invasion in TSC2-deficient cells. Selective SPHK1 antagonist PF543 potently suppressed the viability of TSC2-deficient cells and induced autophagy-mediated cell death. Meanwhile, the cognate receptor S1PR3 was identified to mediating the tumorigenic effects of sphingosine-1-phosphate (S1P). Treatment with TY52156, a selective antagonist for S1PR3, or genetic silencing using S1PR3-siRNA suppressed the viability of TSC2-deficient cells. Both SPHK1 and S1PR3 inhibitors markedly exhibited antitumor effect in a xenograft model of TSC2-null cells, restored autophagy level, and triggered cell death. Together, we identified novel rapamycin-insensitive sphingosine metabolic signatures in TSC2-null LAM cells. Therapeutic targeting of aberrant SPHK1/S1P/S1PR3 signaling may have potent therapeutic benefit for patients with TSC/LAM or other hyperactive mTOR neoplasms with autophagy inhibition.
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影响因子：
16.6
作者：
Nussbaum, Claudia;Bannenberg, Sarah;Keul, Petra;Graeler, Markus H.;Goncalves-de-Albuquerque, Cassiano F.;Korhonen, Hanna;Lipinski, Karin von Wnuck;Heusch, Gerd;de Castro Faria Neto, Hugo C.;Rohwedder, Ina;Goethert, Joachim R.;Prasad, Vysakh Pushpa;Haufe, Guenter;Lange-Sperandio, Baerbel;Offermanns, Stefan;Sperandio, Markus;Levkau, Bodo
通讯作者：
Levkau, Bodo
DOI：
10.1038/nrm.2017.107
发表时间：
2018-03
期刊：
Nature reviews. Molecular cell biology
影响因子：
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作者：
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通讯作者：
Obeid LM
影响因子：
11.2
作者：
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Priolo, Carmen
影响因子：
4.6
作者：
Kumar A;Zamora-Pineda J;Degagné E;Saba JD
通讯作者：
Saba JD
DOI：
10.3390/ph5050514
发表时间：
2012-05-18
期刊：
Pharmaceuticals (Basel, Switzerland)
影响因子：
--
作者：
Chiba K;Adachi K
通讯作者：
Adachi K