Unveiling the therapeutic potential of THC in endometrial cancer

Abstract

[eng] Endometrial cancer represents the most common cancer arising from the uterine cavity and there is little hope for patients with recurrent or metastatic disease. Prior studies of our group reported autophagy pathway as the leading cause of sorafenib anti-cancer treatment resistance in endometrial cancer. Thus, sorafenib sensitive and resistant tumors were analyzed revealing CNR1 overexpression, autophagy overactivation and deregulated lipid metabolism upon sorafenib resistance. Under this scenario, the main objective of this thesis project was to demonstrate that THC could exert anticancer functions in endometrioid endometrial cancer cells. Our in-vitro studies demonstrated that THC triggered cytostatic effects in endometrial cancer cells. Transcriptomic profile analysis unveiled profound changes at a transcriptional level upon THC exposure, reporting alterations in lipid metabolism. Further validations demonstrated a massive accumulation of TAG within lipid droplets upon THC, demonstrating for the first time, the association between THC treatment and lipid droplets in endometrial cancer. Furthermore, complementary in-vitro studies demonstrated the activation of autophagy pathway upon THC exposure. Moreover, our studies demonstrated a direct crosstalk between THC-derived autophagy and lipid droplet synthesis. Furthermore, transcriptomic analysis unveiled ferroptotic cell death signatures upon THC exposure, emphasized in combination with sorafenib. Interestingly, combination treatment reduced cell viability of sorafenib sensitive and resistant cells in-vitro. Furthermore, sorafenib sensitive and resistant tumors derived cells were used to study THC and sorafenib effects in-vivo, reporting that combination treatment drastically reduced tumor growth regardless sorafenib resistance, demonstrating the ability of THC in the reversion of acquired resistance to sorafenib. Altogether, our study sheds light into a new possible therapeutic strategy for advanced and metastatic endometrial cancer patients. Moreover, our study delineates a potential re-sensitization strategy not only for endometrial cancer patients, but potentially for other types of neoplasias in which sorafenib is used in the standard of care.