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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, 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.

SUBMITTER: Kawasaki BT

PROVIDER: S-EPMC2700306 | biostudies-literature | 2009 Jun

REPOSITORIES: biostudies-literature

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

Kawasaki Brian T BT Hurt Elaine M EM Kalathur Madhuri M Duhagon Maria Ana MA Milner John A JA Kim Young S YS Farrar William L WL

The Prostate 20090601 8

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 form ...[more]

PMID: 19204913

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Project description:BackgroundThere has been much interest in targeting intracellular redox pathways as a therapeutic approach for cancer. Given recent data to suggest that the redox status of extracellular protein thiol groups (i.e. exofacial thiols) effects cell behavior, we hypothesized that redox active anti-cancer agents would modulate exofacial protein thiols.Methodology/principal findingsTo test this hypothesis, we used the sesquiterpene lactone parthenolide, a known anti-cancer agent. Using flow cytometry, and western blotting to label free thiols with Alexa Fluor 633 C(5) maleimide dye and N-(biotinoyl)-N-(iodoacetyl) ethylendiamine (BIAM), respectively, we show that parthenolide decreases the level of free exofacial thiols on Granta mantle lymphoma cells. In addition, we used immuno-precipitation techniques to identify the central redox regulator thioredoxin, as one of the surface protein thiol targets modified by parthenolide. To examine the functional role of parthenolide induced surface protein thiol modification, we pretreated Granta cells with cell impermeable glutathione (GSH), prior to exposure to parthenolide, and showed that GSH pretreatment; (a) inhibited the interaction of parthenolide with exofacial thiols; (b) inhibited parthenolide mediated activation of JNK and inhibition of NFkappaB, two well established mechanisms of parthenolide activity and; (c) blocked the cytotoxic activity of parthenolide. That GSH had no effect on the parthenolide induced generation of intracellular reactive oxygen species supports the fact that GSH had no effect on intracellular redox. Together these data support the likelihood that GSH inhibits the effect of parthenolide on JNK, NFkappaB and cell death through its direct inhibition of parthenolide's modulation of exofacial thiols.Conclusions/significanceBased on these data, we postulate that one component of parthenolide's anti-lymphoma activity derives from its ability to modify the redox state of critical exofacial thiols. Further, we propose that cancer cell exofacial thiols may be important and novel targets for therapy.

Project description:BackgroundCancer stem-like cells are proposed to sustain solid tumors by virtue of their capacity for self-renewal and differentiation to cells that comprise the bulk of the tumor, and have been identified for a variety of cancers based on characteristic clonal morphologies and patterns of marker gene expression.MethodsSingle cell cloning and spheroid culture studies were used to identify a population of cancer stem-like cells in the androgen-independent human prostate cancer cell line PC3.ResultsWe demonstrate that, under standard culture conditions, ~10% of PC3 cells form holoclones with cancer stem cell characteristics. These holoclones display high self-renewal capability in spheroid formation assays under low attachment and serum-free culture conditions, retain their holoclone morphology when passaged at high cell density, exhibit moderate drug resistance, and show high tumorigenicity in scid immunodeficient mice. PC3 holoclones readily form spheres, and PC3-derived spheres yield a high percentage of holoclones, further supporting their cancer stem cell-like nature. We identified one gene, FAM65B, whose expression is consistently up regulated in PC3 holoclones compared to paraclones, the major cell morphology in the parental PC3 cell population, and two genes, MFI2 and LEF1, that are consistently down regulated. This molecular profile, FAM65Bhigh/MFI2low/LEF1low, also characterizes spheres generated from parental PC3 cells. The PC3 holoclones did not show significant enriched expression of the putative prostate cancer stem cell markers CD44 and integrin α2β1. PC3 tumors seeded with holoclones showed dramatic down regulation of FAM65B and dramatic up regulation of MFI2 and LEF1, and unexpectedly, a marked increase in tumor vascularity compared to parental PC3 tumors, suggesting a role of cancer stem cells in tumor angiogenesis.ConclusionsThese findings support the proposal that PC3 tumors are sustained by a small number of tumor-initiating cells with stem-like characteristics, including strong self-renewal and pro-angiogenic capability and marked by the expression pattern FAM65Bhigh/MFI2low/LEF1low. These markers may serve as targets for therapies designed to eliminate cancer stem cell populations associated with aggressive, androgen-independent prostate tumors such as PC3.

Dataset Information

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

Publications

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

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