Organochlorine pesticides (OCPs) are widely distributed in the environment and their toxicity is mostly associated with the molecular mechanisms of endocrine disruption and carcinogenesis. It is conceivable to hypothesize that OCPs may exert their toxic effects not only by interfering with the activity of endogenous hormones, but also through the activation of “non-genomic” pathways which cross-talk with other signalling cascades. The hormone resistance, referred as Castration-Resistant Prostate Cancer (CRPC), normally occurs after hormone therapy and leads to PCa transformation into a more aggressive and undifferentiated form. This event is a multifactorial process and seems to involve a crossover between the Androgen Receptor (AR) signalling and other regulatory pathways [Reichert, 2016] like those STAT3-mediated [Bishop et al, 2014]. Moreover, the CRPC development is also due to an altered glucose metabolism and a higher synthesis of one-carbon units. This new cellular condition interferes with energy metabolism by redirecting glycolysis to lactate production and triggering the Warburg effect [Yu et al, 2016]. Organochlorine pesticides (dioxins, lindane, hexachlobenzene) are among the most widespread pollutants and are also known to be endocrine disrupting chemicals, given to their capability to interfere with hormone-related activities. Among organochlorines, particular attention was addressed in investigating the molecular effects of the β- isomer of hexaclorocyclohexane (β-HCH) [Rubini et al., 2018], characterized by a high lipid solubility, environmental persistence and long biological half-lives in human tissues. The cellular impact of β-HCH was evaluated on LNCaP cells (human prostate cancer cells, androgen receptor positive) and obtained results showed that this organochlorine can act as endocrine disruptor on AR activation by interfering with STAT3 mediated regulatory pathways and triggering the synthesis of one- carbon units, leading to the Warburg effect.
beta-HEXACHLOROCYCLOHEXANE MAY INDUCE HORMONE RESISTANCE IN PROSTATE CANCER / Rubini, Elisabetta; Paglia, Giuliano; Altieri, Fabio; Chichiarelli, Silvia; Gullì, Marco; Pacelli Chiara, &; Eufemi, Margherita. - (2019). (Intervento presentato al convegno 2nd Workshop Differentiation and Neoplastic Transformation tenutosi a Florence, Italy).
beta-HEXACHLOROCYCLOHEXANE MAY INDUCE HORMONE RESISTANCE IN PROSTATE CANCER
Rubini Elisabetta;Paglia Giuliano;Altieri Fabio;Chichiarelli Silvia;Gullì Marco;Eufemi Margherita
2019
Abstract
Organochlorine pesticides (OCPs) are widely distributed in the environment and their toxicity is mostly associated with the molecular mechanisms of endocrine disruption and carcinogenesis. It is conceivable to hypothesize that OCPs may exert their toxic effects not only by interfering with the activity of endogenous hormones, but also through the activation of “non-genomic” pathways which cross-talk with other signalling cascades. The hormone resistance, referred as Castration-Resistant Prostate Cancer (CRPC), normally occurs after hormone therapy and leads to PCa transformation into a more aggressive and undifferentiated form. This event is a multifactorial process and seems to involve a crossover between the Androgen Receptor (AR) signalling and other regulatory pathways [Reichert, 2016] like those STAT3-mediated [Bishop et al, 2014]. Moreover, the CRPC development is also due to an altered glucose metabolism and a higher synthesis of one-carbon units. This new cellular condition interferes with energy metabolism by redirecting glycolysis to lactate production and triggering the Warburg effect [Yu et al, 2016]. Organochlorine pesticides (dioxins, lindane, hexachlobenzene) are among the most widespread pollutants and are also known to be endocrine disrupting chemicals, given to their capability to interfere with hormone-related activities. Among organochlorines, particular attention was addressed in investigating the molecular effects of the β- isomer of hexaclorocyclohexane (β-HCH) [Rubini et al., 2018], characterized by a high lipid solubility, environmental persistence and long biological half-lives in human tissues. The cellular impact of β-HCH was evaluated on LNCaP cells (human prostate cancer cells, androgen receptor positive) and obtained results showed that this organochlorine can act as endocrine disruptor on AR activation by interfering with STAT3 mediated regulatory pathways and triggering the synthesis of one- carbon units, leading to the Warburg effect.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
