Ricerc@Sapienza

Prostate cancer (PCa), classified as hormone-related cancer, is a complex multifaceted and biologically heterogeneous disease. At the initial stages, PCa cells are dependent on androgens for their growth and hence effectively combated by androgen deprivation therapy (ADT) until PCa recurs during hormonal therapy and became hormone refractory or castration-resistant prostate cancer (CRPC). Although the role of androgen receptors (AR) signalling in PCa development and progression has been well established, the intrinsic heterogeneity of PCa is due to the presence of additional signalling pathways. These include citokines, growth factors and oxidative stress response, which can modulate the AR pathway. Thus, the onset, progression and hormone-resistance of PCa can be triggered by cellular responses to autocrin and paracrin stimuli, as well as environmental factors, which are able to modulate cell activity. Environmental contamination plays an important role in cancer initiation and progression. Organochlorine pesticides (OCPs), such as beta-hexachlorocyclohexane (ß-HCH), are lipophilic and stable compounds, which are also endocrine-disrupting chemicals (EDCs). Human exposure to EDCs is considered a possible cause for hormone dependent tumours. Different metabolic pathways are often modified in PCa cells to preserve cell division and growth, and are related to the malignancy degree. PCa cells associated to high Gleason score tissues mostly show a metabolic shift, with the production of lactate (Warburg effect). Also OCPs can modulate cellular metabolism and then contribute to the transformation of tumour in a more aggressive form. For this reason we decided to study how OCPs, with a particular attention to ß-HCH, can induce a metabolism shift likely involved in chemo-resistance and in hormone refractory of PCa. Understanding the mechanisms of resistance that cause hormone-naive prostate cancer to progress to castration-resistance is the key to develop future therapies.