DYRK1A suppression restrains Mcl-1 expression and sensitizes NSCLC cells to Bcl-2 inhibitors
| Autor: | Yang-ling Li, Shuang Xu, Dongmei Zhou, Lin-wen Wu, Chong Zhang, Ming-jun Rao, Neng-ming Lin, Zuo-yan Zhang |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
Male
0301 basic medicine Cancer Research Small interfering RNA Lung Neoplasms Sulforhodamine B Antineoplastic Agents Apoptosis Protein Serine-Threonine Kinases NSCLC lcsh:RC254-282 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Western blot Annexin Carcinoma Non-Small-Cell Lung Cell Line Tumor hemic and lymphatic diseases Gene expression medicine Humans RNA Small Interfering neoplasms Aged Cell Proliferation combination medicine.diagnostic_test Chemistry Kinase Cell growth Mcl-1 DYRK1A Middle Aged Protein-Tyrosine Kinases lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens Bcl-2 inhibitor 030104 developmental biology Proto-Oncogene Proteins c-bcl-2 Oncology Drug Resistance Neoplasm 030220 oncology & carcinogenesis Cancer research Myeloid Cell Leukemia Sequence 1 Protein Female Original Article |
| Zdroj: | Cancer Biology & Medicine Cancer Biology & Medicine, Vol 17, Iss 2, Pp 387-400 (2020) |
| ISSN: | 2095-3941 |
| DOI: | 10.20892/j.issn.2095-3941.2019.0380 |
| Popis: | Objective: Mcl-1 overexpression confers acquired resistance to Bcl-2 inhibitors in non-small cell lung cancer (NSCLC), but no direct Mcl-1 inhibitor is currently available for clinical use. Thus, novel therapeutic strategies are urgently needed to target Mcl-1 and sensitize the anti-NSCLC activity of Bcl-2 inhibitors. Methods: Cell proliferation was measured using sulforhodamine B and colony formation assays, and apoptosis was detected with Annexin V-FITC staining. Gene expression was manipulated using siRNAs and plasmids. Real-time PCR and Western blot were used to measure mRNA and protein levels. Immunoprecipitation and immunofluorescence were used to analyze co-localization of dual specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A) and Mcl-1. Results: Suppression of DYRK1A resulted in reduced Mcl-1 expression in NSCLC cells, whereas overexpression of DYRK1A significantly increased Mcl-1 expression. Suppression of DYRK1A did not alter Mcl-1 mRNA levels, but did result in an accelerated degradation of Mcl-1 protein in NSCLC cells. Furthermore, DYRK1A mediated proteasome-dependent degradation of Mcl-1 in NSCLC cells, and DYRK1A co-localized with Mcl-1 in NSCLC cells and was co-expressed with Mcl-1 in tumor samples from lung cancer patients, suggesting that Mcl-1 may be a novel DYRK1A substrate. We showed that combined therapy with harmine and Bcl-2 antagonists significantly inhibited cell proliferation and induced apoptosis in NSCLC cell lines as well as primary NSCLC cells. Conclusions: Mcl-1 is a novel DYRK1A substrate, and the role of DYRK1A in promoting Mcl-1 stability makes it an attractive target for decreasing Bcl-2 inhibitor resistance. |
| Databáze: | OpenAIRE |
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