Bone morphogenetic protein receptor 2 inhibition destabilizes microtubules promoting the activation of lysosomes and cell death of lung cancer cells
| Autor: | Salma K. Jabbour, John Langenfeld, Elaine Langenfeld, Logan Napoli, Jacques Roberge, Arindam Mondal, Youyi Peng, Dongxuan Jia, John A. Gilleran, Christopher Rongo, Zoya Syed, Rachel NeMoyer, Mehul Vora |
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| Rok vydání: | 2020 |
| Předmět: |
Programmed cell death
Lung Neoplasms Cell Survival Quinolones Bone Morphogenetic Protein Receptors Type II Biochemistry Microtubules Microtubule Lysosome medicine Humans Bone morphogenetic protein receptor RNA Small Interfering Molecular Biology Transcription factor Bone Morphogenetic Protein Receptors Type I Cell Proliferation QH573-671 Cell Death Chemistry Research Imidazoles Cell Biology BMPR2 Cell biology medicine.anatomical_structure Pyrimidines Cytoplasm Cancer cell Medicine Pyrazoles Cytology Lysosomes Naphthoquinones Signal Transduction |
| Zdroj: | Cell Communication and Signaling : CCS Cell Communication and Signaling, Vol 19, Iss 1, Pp 1-15 (2021) |
| ISSN: | 1478-811X |
| Popis: | BackgroundRecent 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.MethodsWe 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.ResultsWe 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.ConclusionsThese 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. |
| Databáze: | OpenAIRE |
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