Lupeol triterpene, a novel diet-based microtubule targeting agent: Disrupts survivin/cFLIP activation in prostate cancer cells

Mohammad Saleem, Imtiyaz Murtaza, Olya Witkowsky, Amanda Marie Kohl, Nityanand Maddodi

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31 Scopus citations

Abstract

Recently we showed Lupeol, a triterpene, found in fruits and vegetables inhibits the growth of tumors originated from human androgen-sensitive prostate cancer (CaP) cells and decreases the serum-PSA levels in a mouse model. Here, we provide evidence that Lupeol inhibits the growth of androgen-sensitive as well as androgen-insensitive CaP cells by inducing G2/M cell cycle arrest without exhibiting any toxicity to normal human prostate epithelial cells (PrEC) at the doses at which it kills cancer cells. We observed that Lupeol treatment to LNCaP and DU145 cells resulted in a dose-dependent (i) decrease in the protein levels of Cyclins-A, -B1, -D1, -D2, -E2, cyclin-dependent kinase (cdk)-2 and (ii) increase in the protein level of CDK-inhibitor p21. Since G2/M cell cycle phase is regulated by microtubule assembly, we investigated effect of Lupeol on microtubule assembly, its regulation and down-stream targets in CaP cells. Lupeol treatment significantly modulated the level of (i) microtubule components α-tubulin and β-tubulin, (ii) microtubule-regulatory protein stathmin, and (iii) microtubule-regulatory down-stream target/pro-survival protein survivin. Lupeol treatment also decreased the level of anti-apoptotic protein cFLIP. Finally, Lupeol was observed to significantly decrease the transcriptional activation of survivin and cFLIP genes in CaP cells. We conclude that the Lupeol-induced growth inhibition of CaP cells is a net outcome of simultaneous effects on stathmin, cFLIP, and survivin which results in the disruption of microtubule assembly. We suggest that Lupeol alone or as an adjuvant to other microtubule agents could be developed as a potential agent for the treatment of human CaP.

Original languageEnglish (US)
Pages (from-to)576-582
Number of pages7
JournalBiochemical and Biophysical Research Communications
Volume388
Issue number3
DOIs
StatePublished - Oct 23 2009
Externally publishedYes

Bibliographical note

Funding Information:
This work was supported by United States PHS Grant R03 CA130064 to Mohammad Saleem, Bhat. Author (Imtiyaz Murtaza) was recipient of Overseas Associateship Award (BT/IN/BTON/Nich/09/2007) from Department of Biotechnology, Ministry of Science and Technology, Government of India. We thank Dr. K.M. Wahidur Rahman (Department of Pathology, Wayne State University School of Medicine, USA) for providing pLuc-Survivin plasmid. We thank Dr. Peter Erb (University of Basel, Basel, Switzerland) for providing pGL3-Luc-cFLIP construct.

Keywords

  • G2/M arrest
  • Lupeol
  • Microtubule
  • Prostate cancer
  • Stathmin
  • Survivin
  • cFLIP

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