n2-(1h-indazole-5-yl)-n6-methyl-3-nitropyridine-2-6-diamine and Lung-Neoplasms

The Bcl-2 family protein, Mcl-1 is known to have anti-apoptotic functions, and depletion of Mcl-1 by cellular stresses favors the apoptotic process. Moreover, Mcl-1 levels are frequently increased in various cancer cells, including non-small cell lung cancer (NSCLC), and is implicated in resistance to conventional chemotherapy and in cancer metastasis. In this study, we demonstrated that KRIBB11 accelerates the proteasomal degradation of Mcl-1 in the NSCLC cell line, A549. While KRIBB11 is an inhibitor of HSF1, we found that KRIBB11 induced Mcl-1 degradation in an HSF1-independent manner. Furthermore, this process was triggered via increase ubiquitination by the E3 ligase, Mule, rather than via de-ubiquitination by USP9X. Additionally, we found that Mcl-1 levels were only transiently reduced by KRIBB11: Mcl-1 levels were gradually restored as KRIBB11 activity diminished. However, we found that this effect was blocked in BIS (Bcl-2 interacting cell death suppressor, also called BAG3)-depleted cells, and that BIS prevents Mcl-1 from undergoing HSP70-driven proteasomal degradation, through an interaction with HSP70. Taken together, our results suggest that targeting Mcl-1 with KRIBB11 treatment, while simultaneously downregulating BIS, could be a therapeutic strategy in NSCLC.

Topics: Aminopyridines; Apoptosis; Carcinoma, Non-Small-Cell Lung; DNA-Binding Proteins; Heat Shock Transcription Factors; HSP70 Heat-Shock Proteins; Humans; Indazoles; Lung Neoplasms; Myeloid Cell Leukemia Sequence 1 Protein; Proteasome Endopeptidase Complex; Proteolysis; Transcription Factors; Tumor Cells, Cultured; Tumor Suppressor Proteins; Ubiquitin-Protein Ligases