Splicing variant of AIMP2 as an effective target against chemoresistant ovarian cancer

Area of Science:

• Oncology
• Molecular Biology
• Cancer Therapeutics

Background:

• Chemoresistance significantly hinders effective cancer treatment, particularly in epithelial ovarian cancer (EOC).
• While nuclear factor-kappa B (NF-κB) is implicated in chemoresistance, its complex regulatory network makes direct targeting challenging.
• Aberrant signaling pathways contribute to treatment failure in advanced cancers.

Purpose of the Study:

• To investigate the potential of AIMP2-DX2, a splice variant of AIMP2, as a therapeutic target for chemoresistant EOC.
• To elucidate the mechanism by which AIMP2-DX2 contributes to chemoresistance in EOC.
• To evaluate the efficacy of targeting AIMP2-DX2 using siRNA delivery in vivo.

Main Methods:

• Quantitative analysis of AIMP2-DX2 expression in chemoresistant EOC models (in vitro and in vivo).
• Investigation of the interaction between AIMP2, TRAF2, and tumor necrosis factor alpha (TNF-α) signaling.
• Direct intra-tumoral delivery of siRNA targeting AIMP2-DX2 using microneedles coupled with microendoscopy in mouse models of EOC.
• Assessment of tumor growth rate, apoptosis levels, and TRAF2 expression in treated tumors.

Main Results:

• AIMP2-DX2 was found to be highly expressed in chemoresistant EOC.
• AIMP2-DX2 inhibits the pro-apoptotic function of AIMP2 by competitively binding to TRAF2, thereby modulating NF-κB activity.
• siRNA-mediated downregulation of AIMP2-DX2 significantly suppressed tumor growth in vivo.
• Treatment led to increased apoptosis and reduced TRAF2 levels in ovarian cancer tissues.

Conclusions:

• AIMP2-DX2 is a key mediator of chemoresistance in EOC by disrupting AIMP2-TRAF2-mediated apoptosis.
• Targeting AIMP2-DX2 represents a promising therapeutic strategy for overcoming chemoresistance in EOC.
• The downregulation of AIMP2-DX2 can serve as an effective adjuvant therapy for chemoresistant EOC, particularly those with aberrant NF-κB signaling.