Lupeol triterpene, a novel diet-based microtubule targeting agent: disrupts survivin/cFLIP activation in prostate cancer cells.
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 alpha-tubulin and beta-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.
Saleem
Mohammad
M
School of Medicine and Public Health, University of Wisconsin, 1300 University Avenue, MSC # 4385, Madison, WI 53719, USA. msbhat@wisc.edu
Murtaza
Imtiyaz
I
Witkowsky
Olya
O
Kohl
Amanda Marie
AM
Maddodi
Nityanand
N
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004032:Diet; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D008297:Male; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000378:metabolism; D008870:Microtubules / Q000187:drug effects* / Q000378:metabolism; D053978:Pentacyclic Triterpenes; D011471:Prostatic Neoplasms / Q000378:metabolism*; D000077022:Survivin; D015533:Transcriptional Activation; D014315:Triterpenes / Q000494:pharmacology*; D050257:Tubulin Modulators / Q000494:pharmacology*; D000094042:Lupanes
D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D053978:Pentacyclic Triterpenes; D000077022:Survivin; D014315:Triterpenes; D050257:Tubulin Modulators; C107489:BIRC5 protein, human; C010480:lupeol; D000094042:Lupanes
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