Inactivation of ATP citrate lyase by Cucurbitacin B: A bioactive compound from cucumber, inhibits prostate cancer growth

Cancer Lett. 2014 Jul 10;349(1):15-25. doi: 10.1016/j.canlet.2014.03.015. Epub 2014 Mar 29.

Abstract

Prostate cancer, a leading cause of cancer-related deaths in males, is well recognized as having late disease on-set (mostly at age 60-70) and showing slow/latent disease development, and strategies to prevent cancer formation in late manhood may have significant health impacts. Cucurbitacin B (CuB) is a naturally occurring compound that is found abundantly in cucumbers and other vegetables, and it is known to exert anti-cancer activities (primarily via apoptosis-induction) in several human cancers. However, its chemopreventive potential for prostate cancer has not yet been investigated. Here, we reported that CuB significantly and specifically inhibited prostate cancer cell growth with low IC50 (~0.3 μM; PC-3 and LNCaP), accompanied by marked apoptosis (Caspase 3/7 activation, PARP cleavage, increase of Annexin V-Alexa Fluor 488 (Alexa488)+ cells and accumulation of Sub-G0/G1 population), whereas normal human prostate epithelial cells (PrEC) were CuB-insensitive. Using a chemopreventive model, pre-treatment of mice with CuB (2 weeks before PC-3 prostate cancer cell implantation) significantly reduced the rate of in vivo tumor-formation. A 79% reduction in tumor size (accompanied by marked in situ apoptosis) was observed in the CuB-treated group (with no noticeable toxicity) vs. controls at day 31. Strikingly, mechanistic investigations demonstrated that CuB drove dose-dependent inhibition of ATP citrate lyase phosphorylation (ACLY; an important enzyme for cancer metabolism) both in vitro and in the CuB-chemopreventive mouse model. Importantly, ACLY over-expression abrogated CuB's apoptotic effects in prostate cancer cells, confirming ACLY as a direct target of CuB. Thus, CuB harbors potent chemopreventive activity for prostate cancer, and we revealed a novel anti-tumor mechanism of CuB via inhibition of ACYL signaling in human cancer.

Keywords: ATP citrate lyase; Apoptosis; Cucurbitacin B; Prostate cancer; Xenografts.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • ATP Citrate (pro-S)-Lyase / metabolism*
  • Animals
  • Antineoplastic Agents / pharmacology
  • Apoptosis / drug effects
  • Biological Factors / pharmacology
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Cucumis sativus / chemistry
  • Down-Regulation / drug effects
  • Enzyme Activation / drug effects
  • Epithelial Cells / drug effects
  • Epithelial Cells / metabolism
  • Humans
  • Male
  • Mice
  • Mice, Nude
  • Phosphorylation / drug effects
  • Plant Extracts / pharmacology
  • Prostate / drug effects
  • Prostate / metabolism
  • Prostatic Neoplasms / drug therapy*
  • Prostatic Neoplasms / metabolism
  • Triterpenes / pharmacology*

Substances

  • Antineoplastic Agents
  • Biological Factors
  • Plant Extracts
  • Triterpenes
  • cucurbitacin B
  • ATP Citrate (pro-S)-Lyase