Effects of the sesquiterpene lactone parthenolide on prostate tumor‐initiating cells: An integrated molecular profiling approach

Abstract

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, β1-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-α, 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.

Inhibition of Myb-dependent gene expression by the sesquiterpene lactone mexicanin-I

“…The STL parthenolide inhibits the activation of the mim-1 gene by v-Myb Kawasaki et al 28 have recently investigated the inhibitory effects of the STL parthenolide on a prostate cancer cell line. They identified several potential targets of parthenolide, one of which was the transcription factor c-Myb.…”

Characterisation of a novel cell line (CSQT-2) with high metastatic activity derived from portal vein tumour thrombus of hepatocellular carcinoma

“…M21(i(14q)) i(14)(q10) M22(der(15)) add(15)(?::pter-q24::?) M23 (der(15;22)) der (15) Characterisation of a novel cell line (CSQT-2) T Wang et al Moreover, as is well-known, the theory of cancer stem cells argues that a cancer mass is built up by a relatively tiny portion of the total tumour, called cancer stem cells or TIC (Guglielmi et al, 1998;Bansal and Banerjee, 2009;Kawasaki et al, 2009;Tu et al, 2009). The previous research on HCC TICs found that we could separate or enrich HCC TICs through specific staining for cell surface markers, such as CD133, CD90 and EpCAM (Yang et al, 2008a, b;Yamashita et al, 2009;Yeh et al, 2009;Yoshikawa et al, 2009;Zhu et al, 2009).…”

Towards novel paradigms for cancer therapy

“…It is important to emphasize that natural compounds have also been reported to target TICs selectively, with parthenolide (PTL) being the first such compound described (Guzman et al, 2005(Guzman et al, , 2007Steele et al, 2006;Hassane et al, 2008;Kawasaki et al, 2009). PTL is a sesquiterpene lactone found in feverfew (Chrysanthemum parthenium), which has been traditionally used to treat migraine and rheumatoid arthritis and exerts activity as nuclear factor-kB inhibitor, p53 activator (via ubiquitination of MDM2, mouse double minute 2-p53 binding protein homolog), DNMT1 (DNA (cytosine-5-)-methyltransferase 1) inhibitor and promoter of HDAC1 depletion by proteosome degradation (Gopal et al, 2007).…”