DYRK1A suppression restrains Mcl-1 expression and sensitizes NSCLC cells to Bcl-2 inhibitors

Yangling Li, Dongmei Zhou, Shuang Xu, et al.

Abstract


Objective: Mcl-1 overexpression confers acquired resistance to Bcl-2 inhibitors in non-small cell lung cancer (NSCLC), but no directMcl-1 inhibitor is currently available for clinical use. Thus, novel therapeutic strategies are urgently needed to target Mcl-1 andsensitize the anti-NSCLC activity of Bcl-2 inhibitors.

Methods: Cell proliferation was measured using sulforhodamine B and colony formation assays, and apoptosis was detected withAnnexin V-FITC staining. Gene expression was manipulated using siRNAs and plasmids. Real-time PCR and Western blot were usedto measure mRNA and protein levels. Immunoprecipitation and immunofluorescence were used to analyze co-localization of dualspecificity 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 DYRK1Asignificantly increased Mcl-1 expression. Suppression of DYRK1A did not alter Mcl-1 mRNA levels, but did result in an accelerateddegradation of Mcl-1 protein in NSCLC cells. Furthermore, DYRK1A mediated proteasome-dependent degradation of Mcl-1 inNSCLC cells, and DYRK1A co-localized with Mcl-1 in NSCLC cells and was co-expressed with Mcl-1 in tumor samples from lungcancer patients, suggesting that Mcl-1 may be a novel DYRK1A substrate. We showed that combined therapy with harmine andBcl-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 targetfor decreasing Bcl-2 inhibitor resistance.

Cite this article as: Li Y, Zhou D, Xu S, Rao M, Zhang Z, Wu L et al. DYRK1Asuppression restrains Mcl-1 expression and sensitizes NSCLC cells to Bcl-2inhibitors. Cancer Biol Med. 2020; 17: 387-400. doi: 10.20892/j.issn.2095-3941.2019.0380


Keywords


DYRK1A; Mcl-1; NSCLC; combination; Bcl-2 inhibitor

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