Simvastatin-Mediated Molecular Mechanisms Underlying the Growth Inhibition of Testicular Leydig Tumour Cells

Abstract

Leydig cell tumours (LCTs) are uncommon stromal neoplasms of the testis, accounting for less than 3% of all gonadal cancers. Most of them are benign, but the malignant ones are very aggressive without specific effective treatment. Several studies reported pharmacologic insight into the use of statins as anti-tumour agents, but their efficacy on LCTs has not been investigated. Previously, we emphasised the central role of insulin-like growth factor 1 (IGF1)/insulin-like growth factor 1 receptor (IGF1R) signalling in Leydig cell tumorigenesis; here, we showed that simvastatin reduces cell proliferation, determines cell cycle arrest at the G1 phase, and induces reactive oxygen species (ROS) accumulation and apoptosis in R2C and LC540 rat Leydig tumour cells. Furthermore, it prevents isoprenoid farnesyl pyrophosphate (FPP) formation and decreases IGF1R expression, leading to the breakdown of the IGF1R signalling pathway. Importantly, we observed that simvastatin synergised with cisplatin in reducing tumour cell proliferation. Collectively, these data suggest that simvastatin is a potential anticancer drug capable of counteracting LCT growth, and it could be proposed as an adjuvant for chemotherapy in LCT treatment.