We have shown previously that Gugggulsterone (Gug) inhibits growth of cultured LNCaP and PC-3 human
prostate cancer cells by causing apoptosis induction in association with
reactive-oxygen species (ROS)-dependent activation of
c-Jun N-terminal kinase (JNK). The present study builds upon the novel observations and now reveals a novel mechanism of Gug-anticancer activity that
ATP citrate lyase (ACLY)-regulated Akt inactivation is involved in Gug-mediated inhibition of
prostate cancer growth. Oral gavage of Gug significantly retarded the growth of PC-3 xenografts in athymic mice without causing
weight loss and any other side effects. The Gug-induced apoptosis was associated with remarkably down-regulation of Akt and ACLY in both
cancer cells and xenografts
tumor tissue of Gug-treated group. Ectopic expression of constitutively active Akt conferred significant protection against Gug-mediated apoptotic cell death in both
cancer cells. Moreover, the Gug-induced apoptosis, and Akt and ACLY inactivation in PC-3 and LNCaP cells was intensified by
siRNA-based knockdown of ACLY
protein level and by pharmacological inhibition of ACLY, or was protected by the ectopic expression of ACLY. In conclusion, the present study reveals a novel mechanism of Gug-anticancer activity that Gug-inhibited
prostate cancer growth is regulated by ACLY/Akt signaling axis.