IGF2R: a new player in the IGF2 loop sustaining adrenocortical carcinogenesis

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• Adrenocortical carcinoma (ACC) is often linked to IGF2 overexpression, with research focusing on IGF1R and IR.
• IGF2 receptor (IGF2R), previously considered a tumor suppressor, is now implicated as a pro-tumorigenic factor in other cancers via SphK activation.
• The role of IGF2R in ACC and its therapeutic potential remains largely unexplored.

Purpose of the Study:

• To investigate the role of IGF2R in ACC cells.
• To elucidate the mechanism of IGF2R action in ACC.
• To evaluate IGF2R and SphK inhibitors as potential ACC therapies.

Main Methods:

• In vitro study using 4 ACC cell lines and 3 primary ACC cultures.
• Analysis of IGF2R, IGF2, and IGF1R expression in normal and tumoral adrenal tissues and cell lines.
• Assessment of IGF2R downregulation/overexpression and IGF2R/SphK inhibition effects on cell viability, proliferation, apoptosis, and cortisol secretion.

Main Results:

• IGF2R was overexpressed in ACC tissues and correlated with IGF2 and IGF1R expression.
• In vitro assays confirmed IGF2R's pro-mitotic role and SphK activation.
• IGF2R antibody, safingol, and fingolimod demonstrated anti-tumoral effects, reducing proliferation and viability while inducing apoptosis and decreasing cortisol secretion.

Conclusions:

• IGF2R exhibits a tumorigenic effect in ACC through SphK activation.
• Pharmacological inhibition of the IGF2R/SphK pathway effectively controlled ACC growth in vitro.
• The IGF2R/SphK pathway represents a promising novel therapeutic target for ACC.