Abstract
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.
Highlights
As a primary bone cancer, multiple myeloma (MM) commonly occurs in the elderly population, which has an increasing incidence and can cause hematologic malignancy [1, 2]
These results indicated that BTZ inhibited cell proliferation by upregulating Activating transcription factor 3 (ATF3)
We found that BTZ inhibited cell proliferation and expression of ATF3 was significantly increased under BTZ treatment in a dose-dependent manner
Summary
As a primary bone cancer, multiple myeloma (MM) commonly occurs in the elderly population (aged ≥70 years), which has an increasing incidence and can cause hematologic malignancy [1, 2]. The therapeutic options for MM patients are mainly based on age, tumor stage, and comorbidities [3]. A frequently used chemotherapeutic drug in MM is bortezomib (BTZ), it acts as a proteasome inhibitor and interferes with the degradation of misfolded proteins [4, 5]. BTZ suppresses ubiquitin-dependent protein degradation and preferentially kills various tumor cells [6]. BTZ sensitizes cells to oxidative damage by the iron status to enhance proteasome inhibition [7, 8]. Despite the unsurpassed anti-tumor activity of BTZ for MM [9], drug resistance
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