ATO Increases ROS Production and Apoptosis of Cells by Enhancing Calpain-Mediated Degradation of the Cancer Survival...

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• Transglutaminase 2 (TG2) is a key factor in cancer cell survival, promoting drug resistance, metastasis, and angiogenesis.
• All-trans retinoic acid (ATRA) and chemotherapy are standard for acute promyelocytic leukemia (APL), but arsenic trioxide (ATO) shows improved outcomes, alone or with ATRA.
• ATO induces cytotoxicity through oxidative stress, genotoxicity, and altered signaling pathways.

Purpose of the Study:

• To investigate the role of TG2 in ATO and ATRA-induced apoptosis in leukemia cells.
• To elucidate the mechanisms by which ATO and ATRA affect TG2 expression and activity.
• To assess the therapeutic potential of targeting TG2 in cancer treatment.

Main Methods:

• Utilized ATRA-differentiated NB4 leukemia cells with and without TG2 deletion.
• Administered ATO and ATRA treatments, alone and in combination.
• Measured reactive oxygen species (ROS) production, apoptosis ratios, NRF2 transcription factor levels, and calpain activity.
• Analyzed TG2 protein expression in leukemia cells, MCF-7 cells, and primary peripheral blood mononuclear cells.

Main Results:

• ATO treatment increased ROS production and apoptosis in ATRA-differentiated leukemia cells, with enhanced effects in TG2-deleted cells.
• Combined ATRA + ATO treatment upregulated NRF2 and calpain activity, leading to TG2 degradation and reduced survival in wild-type leukemia cells.
• ATO treatment induced TG2 degradation in MCF-7 cells and primary peripheral blood mononuclear cells, sensitizing them to apoptosis.

Conclusions:

• TG2 degradation is a key mechanism by which ATO, particularly in combination with ATRA, induces apoptosis in leukemia cells.
• Targeting TG2 degradation represents a potential therapeutic strategy to enhance the efficacy of ATO and ATRA treatments in various cancer types.
• ATO treatment sensitizes non-leukemia cells to apoptosis by reducing TG2 expression, suggesting broader therapeutic applications.