Endocrine Abstracts

Introduction: The insulin-like growth factor-I receptor (IGF-IR) plays a key role in regulating growth, survival and invasion of several human malignancies including prostate cancer. In prostate cancer cells, the IGF-IR expression is upregulated by androgens through a nongenotropic signaling unresponsive to antiandrogens and requiring AMP-response element-binding protein (CREB) activation. This mechanism sensitizes cells to the proliferative and protumor effects of IGF-I. Metformin, a widely used antidiabetic drug with pleiotropic activity, has been shown to be anti-mitogenic in several cancer cells, partially through the activation of AMP-activated protein kinase (AMPK).

Aim: We investigated whether metformin could affect androgen-induced IGF-IR upregulation in prostate cancer cells.

Methods and results: Using the androgen-sensitive LNCaP prostate cancer cells, we found that metformin specifically inhibits the androgen-mediated upregulation of IGF-IR mRNA and protein levels by blocking the mTOR/p70S6K pathway. These effects were only partially dependent on AMPK activation. Indeed, in the same cells, after knocking-down AMPK, metformin was still able to inhibit the IGF-IR upregulation induced by androgens. Furthermore, in 293HEK cells cotrasfected with constructs encoding for the androgen receptor and the full length IGF-IR promoter, metformin markedly reduced the androgen-stimulated IGF-IR promoter activity by inhibiting CRE activity and CREB phosphorylation at Ser133.

Conclusion: Metformin inhibits androgen-induced nongenotropic IGF-IR upregulation by acting through the inhibition of mTOR/p70S6K pathway, in a manner partially dependent on AMPK activation. These data open promising perspectives for prostate cancer treatment as they suggest that metformin may be a useful adjunct to the classic therapy with antiandrogens.

Declaration of interest: The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research project.

Funding: This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.