Bortezomib Inhibits Multiple Myeloma Cells by Transactivating ATF3 to Trigger miR-135a-5p-Dependent Apoptosis

Multiple myeloma (MM) is a malignant cancer with an increasing in incidence that can be alleviated through bortezomib (BTZ) treatment. Activating transcription factor 3 (ATF3) plays a major role in cancer development. Moreover, microRNAs (miRNAs) regulate carcinogenic pathways, apoptosis, and programmed necrotic cell death. However, the detailed mechanism by which ATF3 modulates BTZ drug sensitivity/resistance remains elusive. In the current study, expression of ATF3 was significantly increased under BTZ treatment in a dose-dependent manner in MM cell lines. In addition, ATF3 could regulate cell apoptosis under BTZ treatment. The effect of ATF3 was negatively regulated by its binding miRNA, miR-135a-5p. When either ATF3 was silenced or miR-135a-5p mimics were added to MM cells, they partially lost sensitivity to BTZ treatment. This was accompanied by low levels of Noxa, CHOP, and DR5, and a decrease in mitochondrial membrane potential. These results revealed the combinatorial regulatory patterns of ATF3 and miR-135a-5p in the regulatory protein interactome, which indicated a clinical significance of the miR-135a-5p-ATF3 protein interaction network in BTZ therapy. This study provides potential evidence for further investigation into BTZ resistance.

Automated summary

This study found that ATF3 increased and regulated cell apoptosis in the process of bortezomib treatment, while being negatively regulated by miR-135a-5p. These results reveal the combinatorial regulatory patterns of ATF3 and miR-135a-5p in the regulatory protein interactome, indicating the clinical significance of the miR-135a-5p-ATF3 protein interaction network in bortezomib therapy.