Papel de AMPK y la regulación metabólica en la resistencia del cáncer de próstata

Abstract

Prostate cancer (PCa) is the second leading cause of cancer death in men and its incidence is progressively increasing over the years due to the increased life expectancy of the population. One of the first therapeutic strategies used in the advanced stages of the disease is the androgen deprivation therapy (ADT). This is effective until the tumour becomes hormonally independent and progresses to a more aggressive stage called castration-resistant prostate cancer, for which therapies are limited. In this case, chemotherapy based on taxanes such as docetaxel is used. However, despite the good initial response of patients to these drugs, the high doses used over a prolonged period of time contribute to the development of resistance and side effects. In addition, in recent years, the deregulation of tumour suppressor genes and oncogenes has been linked to changes in cellular metabolism. The AMP-activated kinase (AMPK), considered a sensor and a key regulator of energy homeostasis, is involved in a large number of metabolic disorders including cancer. For this reason, in this Doctoral Thesis, we studied the role of AMPK in therapysensitive and therapy-resistant prostate cancer. Our results support that the activation of AMPK by capsaicin (CAP), the alkaloid responsible for the hot sensation of peppers of the genus Capsicum, has an antitumor effect in PCa cells. This effect is less potent in tumor cells lacking the LKB1 protein. The knockdown of the canonical CAP receptor, TRPV1, also prevents AMPK activation and, consequently, the CAP-induced antitumor effect. Therefore, the TRPV1/LKB1/AMPK signalling pathway is involved in CAP’s antitumor effect on PCa cells. CAP also can sensitize PCa cells to docetaxel, through activation of the AMPK pathway and inhibition of the PI3K/AKT/mTOR pathway. Therefore, we observe a decrease in AMPK expression and activation in PCa cells maintained in absence of androgens for a prolonged period. The hormone deprivation, in turn, promotes the increase of neuroendocrine (NE) markers and the acquisition of cancer stem cell (CSCs) properties, both phenomena related to PCa resistance to therapy. Among the acquired CSCs properties, we highlight the increase of markers such as ALDH1A1, ABCB1A, CD133, NANOG and OCT4, the ability to differentiate to other cell lineages and resistance to conventional chemotherapeutics. The activation and overexpression of AMPK in CSC-like cells decreases the expression of NE and CSCs markers and sensitizes them to therapy counteracting chemoresistance. In this Doctoral Thesis, we can conclude that AMPK is an important therapeutic target in the treatment of therapy-sensitive and therapy-resistant PCa and that it is involved in prostate cell reprogramming.