CEMIP promotes extracellular matrix-detached prostate cancer cell survival by inhibiting ferroptosis.
CEMIP promotes extracellular matrix-detached prostate cancer cell survival by inhibiting ferroptosis.
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从细胞外基质（ECM）脱离的细胞可以触发不同的细胞死亡模式，并且ECM脱离的细胞的存活是转移级联的先决条件之一。铁凋亡是铁依赖性程序性细胞死亡的一种形式，最近发现与基质分离的癌细胞有关。然而，ECM脱离细胞逃避铁凋亡的分子机制尚未完全了解。在这里，我们观察到细胞迁移诱导蛋白（CEMIP）上调通过促进前列腺癌（PCa）细胞中的胱氨酸摄取促进ECM分离期间的铁凋亡抗性。同时，沉默CEMIP导致其失去促进胱氨酸摄取和抑制铁凋亡的能力。从机制上讲，CEMIP与三磷酸肌醇受体3型（ITPR 3）的相互作用调节钙离子（Ca 2+）从内质网的泄漏，激活钙/钙调蛋白依赖性蛋白激酶II（CaMK II），这进一步促进核因子红细胞2相关因子2（NRF 2）磷酸化和核定位，导致PCa细胞中溶质载体家族7成员11（SLC 7A 11）（谷氨酸/胱氨酸反向转运蛋白）的转录升高。我们的研究结果描绘了CEMIP在ECM脱离期间抗铁下垂中的新作用，并为转移性PCa的治疗策略提供了新的见解。铁凋亡是由前列腺癌细胞中的ECM脱离触发的，而存活的细胞呈现出铁凋亡抗性表型。抑制CEMIP表达通过抑制ITPR 3/CaMKII/NRF 2/SLC 7A 11途径促进铁凋亡而导致分离的细胞死亡。
Cells detached from the extracellular matrix (ECM) can trigger different modes of cell death, and the survival of ECM‐detached cells is one of the prerequisites for the metastatic cascade. Ferroptosis, a form of iron‐dependent programmed cell death, has recently been found to be involved in matrix‐detached cancer cells. However, the molecular mechanisms by which ECM‐detached cells escape ferroptosis are not fully understood. Here, we observed that cell migration‐inducing protein (CEMIP) upregulation facilitates ferroptosis resistance during ECM detachment by promoting cystine uptake in prostate cancer (PCa) cells. Meanwhile, silencing CEMIP causes it to lose its ability to promote cystine uptake and inhibit ferroptosis. Mechanistically, the interaction of CEMIP with inositol 1,4,5‐trisphosphate receptor type 3 (ITPR3) modulates calcium ion (Ca2+) leakage from the endoplasmic reticulum, activating calcium/calmodulin‐dependent protein kinase II (CaMKII), which further facilitates nuclear factor erythroid 2‐related factor 2 (NRF2) phosphorylation and nuclear localization, leading to elevated transcription of solute carrier family 7 member 11 (SLC7A11), a glutamate/cystine antiporter, in PCa cells. Our findings delineate a novel role of CEMIP in ferroptosis resistance during ECM detachment and provide new insights into therapeutic strategies for metastatic PCa. Ferroptosis was triggered by ECM detachment in prostate cancer cells, while the survival cells presented a ferroptosis‐resistant phenotype. Suppressing CEMIP expression led to detached cell death by boosting ferroptosis through inhibiting the ITPR3/CaMKII/NRF2/SLC7A11 pathway.
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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
锚固的丧失主要诱导非典型局灶性粘附激酶信号下人类乳腺上皮细胞系中的非凋亡细胞死亡。
影响因子：
9
作者：
Ishikawa F;Ushida K;Mori K;Shibanuma M
通讯作者：
Shibanuma M
影响因子：
8.8
作者：
Mason, Joshua A.;Cockfield, Jordan A.;Schafer, Zachary T.
通讯作者：
Schafer, Zachary T.
影响因子：
7.2
作者：
Bhattacharyya, Moitrayee;Karandur, Deepti;Kuriyan, John
通讯作者：
Kuriyan, John
影响因子：
--
作者：
Bellezza I;Scarpelli P;Pizzo SV;Grottelli S;Costanzi E;Minelli A
通讯作者：
Minelli A