Bone morphogenetic protein receptor 2 inhibition destabilizes microtubules promoting the activation of lysosomes and cell death of lung cancer cells.
Bone morphogenetic protein receptor 2 inhibition destabilizes microtubules promoting the activation of lysosomes and cell death of lung cancer cells.
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骨形态发生蛋白受体2的抑制破坏微管的稳定性，促进溶酶体的激活和肺癌细胞的死亡。
DOI：
10.1186/s12964-021-00743-w
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发表时间：
2021-09-25
期刊：
影响因子：
--
通讯作者：
Langenfeld J
中科院分区：
文献类型：
--
作者：
Mondal A;NeMoyer R;Vora M;Napoli L;Syed Z;Langenfeld E;Jia D;Peng Y;Gilleran J;Roberge J;Rongo C;Jabbour SK;Langenfeld J
最近的研究表明，骨形态发生蛋白受体2(BMPR2)独立于BMP 1型受体(BMPR1)或Smad-1/5转录因子调节癌细胞的存活信号事件。BMPR2转运蛋白的突变导致BMP信号过度活跃，从而导致BMPR2稳定微管而导致的神经系统疾病。目前还不知道BMPR2是否调节癌细胞中的微管，以及这对细胞存活有什么影响。目前也不知道BMPR2转运的改变是否会影响BMPR2抑制剂的活性和反应。我们利用了BMPR2 siRNA和BMP受体抑制剂JL5和Ym155，它们减少了BMPR2信号转导并导致其错误定位到细胞质。利用耐JL5的MDA-MD-468细胞系和敏感的肺癌细胞系，我们研究了BMPR2抑制对BMPR2错定位于细胞质、微管失稳、溶酶体激活和细胞存活的影响。我们表明，BMPR2的抑制破坏了微管的稳定。微管的不稳定导致溶酶体的激活。激活的溶酶体通过使BMPR2错误定位到细胞质和/或溶酶体来降解，从而进一步降低BMPR2信号转导。氯喹抑制溶酶体可减少BMPR2向溶酶体的转运和BMPR2抑制剂诱导的细胞死亡。此外，在抵抗JL5诱导的细胞死亡的MDA-MD-468细胞中，BMPR2主要定位于细胞质中。经JL5处理后，BMPR2不能定位于细胞质和/或溶酶体，也不破坏微管的稳定性或激活溶酶体。这些研究表明，BMPR2的抑制破坏了促进癌细胞死亡的微管的稳定，这涉及到溶酶体的激活。如果BMPR2主要定位于细胞质和/或不能定位于溶酶体进行降解，则可能发生对靶向BMPR2的小分子的耐药性。视频摘要在线版本包含可在10.1186/s12964-021-00743-w上查阅的补充材料。
Recent studies have shown that bone morphogenetic protein receptor 2 (BMPR2) regulates cell survival signaling events in cancer cells independent of the BMP type 1 receptor (BMPR1) or the Smad-1/5 transcription factor. Mutations in BMPR2 trafficking proteins leads to overactive BMP signaling, which leads to neurological diseases caused by BMPR2 stabilization of the microtubules. It is not known whether BMPR2 regulates the microtubules in cancer cells and what effect this has on cell survival. It is also not known whether alterations in BMPR2 trafficking effects activity and response to BMPR2 inhibitors. We utilized BMPR2 siRNA and the BMP receptor inhibitors JL5 and Ym155, which decrease BMPR2 signaling and cause its mislocalization to the cytoplasm. Using the JL5 resistant MDA-MD-468 cell line and sensitive lung cancer cell lines, we examined the effects of BMPR2 inhibition on BMPR2 mislocalization to the cytoplasm, microtubule destabilization, lysosome activation and cell survival. We show that the inhibition of BMPR2 destabilizes the microtubules. Destabilization of the microtubules leads to the activation of the lysosomes. Activated lysosomes further decreases BMPR2 signaling by causing it to mislocalizated to the cytoplasm and/or lysosome for degradation. Inhibition of the lysosomes with chloroquine attenuates BMPR2 trafficking to the lysosome and cell death induced by BMPR2 inhibitors. Furthermore, in MDA-MD-468 cells that are resistant to JL5 induced cell death, BMPR2 was predominately located in the cytoplasm. BMPR2 failed to localize to the cytoplasm and/or lysosome following treatment with JL5 and did not destabilize the microtubules or activate the lysosomes. These studies reveal that the inhibition of BMPR2 destabilizes the microtubules promoting cell death of cancer cells that involves the activation of the lysosomes. Resistance to small molecules targeting BMPR2 may occur if the BMPR2 is localized predominantly to the cytoplasm and/or fails to localize to the lysosome for degradation. Video Abstract The online version contains supplementary material available at 10.1186/s12964-021-00743-w.
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影响因子：
37.3
作者：
Augeri DJ;Langenfeld E;Castle M;Gilleran JA;Langenfeld J
通讯作者：
Langenfeld J
影响因子：
8.4
作者：
NeMoyer, Rachel;Mondal, Arindam;Langenfeld, John
通讯作者：
Langenfeld, John
影响因子：
8
作者：
Newman, Jenna H.;Augeri, David J.;Langenfeld, John
通讯作者：
Langenfeld, John
影响因子：
3
作者：
Glaros, Trevor G.;Stockwin, Luke H.;Newton, Dianne L.
通讯作者：
Newton, Dianne L.
影响因子：
4.7
作者：
Langenfeld, EM;Calvano, SE;Langenfeld, J
通讯作者：
Langenfeld, J