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

Area of Science:

• Oncology
• Molecular Biology
• Pharmacology

Background:

• Multiple myeloma (MM) is a hematologic malignancy with increasing incidence.
• Bortezomib (BTZ) is a key therapeutic agent for MM.
• The precise mechanisms of BTZ drug resistance, particularly involving transcription factors and microRNAs, require further elucidation.

Purpose of the Study:

• To investigate the role of Activating Transcription Factor 3 (ATF3) in modulating BTZ sensitivity in MM.
• To explore the regulatory relationship between ATF3 and microRNA-135a-5p (miR-135a-5p) in the context of BTZ treatment.
• To elucidate the molecular mechanisms underlying ATF3-mediated regulation of BTZ response.

Main Methods:

• Cultured MM cell lines were treated with varying doses of BTZ.
• Expression levels of ATF3 and miR-135a-5p were analyzed under BTZ treatment.
• ATF3 gene silencing and miR-135a-5p mimic transfection were performed.
• Apoptosis, mitochondrial membrane potential, and expression of key apoptosis-related genes (Noxa, CHOP, DR5) were assessed.

Main Results:

• ATF3 expression increased dose-dependently with BTZ treatment in MM cells.
• ATF3 modulated MM cell apoptosis in response to BTZ.
• miR-135a-5p negatively regulated ATF3 expression.
• Silencing ATF3 or overexpressing miR-135a-5p reduced MM cell sensitivity to BTZ, decreasing Noxa, CHOP, and DR5 levels and mitochondrial membrane potential.

Conclusions:

• The miR-135a-5p-ATF3 axis plays a significant role in regulating MM cell sensitivity to bortezomib.
• This interaction network provides potential targets for overcoming BTZ resistance in multiple myeloma.
• Further research into this regulatory network may offer novel therapeutic strategies for MM treatment.