Effects of the sesquiterpene lactone parthenolide on prostate tumor-initiating cells: An integrated molecular profiling approach.
Recent evidence suggests tumor-initating cells (TICs), also called cancer stem cells, are responsible for tumor initiation and progression; therefore, they represent an important cell population for development of future anti-cancer therapies. In this study, we show that the sesquiterpene lactone parthenolide (PTL) is cytotoxic to prostate TICs isolated from prostate cancer cell lines: DU145, PC3, VCAP, and LAPC4, as well as primary prostate TICs. Furthermore, PTL inhibited TIC-driven tumor formation in mouse xenografts. Using an integrated molecular profiling approach encompassing proteomics, profiles of activated transcription factors and genomics we ascertained the effects of PTL on prostate cancer cells. In addition to the previously described effects of PTL, we determined that the non-receptor tyrosine kinase src, and many src signaling components, including: Csk, FAK, beta1-arrestin, FGFR2, PKC, MEK/MAPK, CaMK, ELK-1, and ELK-1-dependent genes are novel targets of PTL action. Furthermore, PTL altered the binding of transcription factors important in prostate cancer including: C/EBP-alpha, fos related antigen-1 (FRA-1), HOXA-4, c-MYB, SNAIL, SP1, serum response factor (SRF), STAT3, X-box binding protein-1 (XBP1), and p53. In summary, we show PTL is cytotoxic to prostate TICs and describe the molecular events of PTL-mediated cytotoxicity. Therefore, PTL represents a promising therapeutic for prostate cancer treatment.
Kawasaki
Brian T
BT
Cancer Stem Cell Section, Laboratory of Cancer Prevention, Center for Cancer Research, National Cancer Institute at Frederick (NCI-Frederick), National Institutes of Health,1050Boyles Street, Frederick, MD 21702, USA.
Hurt
Elaine M
EM
Kalathur
Madhuri
M
Duhagon
Maria Ana
MA
Milner
John A
JA
Kim
Young S
YS
Farrar
William L
WL
D000818:Animals; D015703:Antigens, CD / Q000235:genetics; D045744:Cell Line, Tumor; D005434:Flow Cytometry; D020869:Gene Expression Profiling / Q000379:methods; D006801:Humans; D018960:Hyaluronan Receptors / Q000235:genetics; D008297:Male; D051379:Mice; D009363:Neoplasm Proteins / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D011467:Prostate / Q000378:metabolism / Q000473:pathology*; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D012334:RNA, Neoplasm / Q000235:genetics / Q000302:isolation & purification; D012717:Sesquiterpenes / Q000494:pharmacology*; D014158:Transcription, Genetic
D015703:Antigens, CD; D018960:Hyaluronan Receptors; D009363:Neoplasm Proteins; D012334:RNA, Neoplasm; D012717:Sesquiterpenes; C002669:parthenolide