PC-SPES: A unique inhibitor of proliferation of prostate cancer cells in vitro and in vivo

Kubota, Tetsuya; Hisatake, Junichi; Hisatake, Yasuko; Said, Jonathan; Chen, Sophie S.; Holden, Stuart; Taguchi, Hirokuni; Koeffler, H. Phillip

doi:10.1002/(sici)1097-0045(20000215)42:3<163::aid-pros1>3.0.co;2-w

Cited by 81 publications

(36 citation statements)

References 35 publications

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“…Surprisingly, we observed the cumulative effect of PKD1 and E-cadherin knockdown on proliferation of DU-145 cells as well, which did not have detectable levels of E-cadherin by Western blot. Although DU-145 cells were considered to be E-cadherin negative, recent publications demonstrate that DU-145 cells do express E-cadherin, albeit at low levels [Kubota et al, 2000;Kwok et al, 2005]. The results of these experiments suggest that low levels of E-cadherin may be sufficient to influence cellular phenotype.…”

Section: Discussionmentioning

confidence: 99%

β‐catenin mediates alteration in cell proliferation, motility and invasion of prostate cancer cells by differential expression of E‐cadherin and protein kinase D1

Syed

Mak

et al. 2007

J of Cellular Biochemistry

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We have previously demonstrated that Protein Kinase D1 (PKD1) interacts with E-cadherin and is associated with altered cell aggregation and motility in prostate cancer (PC). Because both PKD1 and E-cadherin are known to be dysregulated in PC, in this study we investigated the functional consequences of combined dysregulation of PKD1 and E-cadherin using a panel of human PC cell lines. Gainand loss of function studies were carried out by either transfecting PC cells with fulllength E-cadherin and/or PKD1 cDNA or by protein silencing by siRNAs, respectively. We studied major malignant phenotypic characteristics including cell proliferation, motility, and invasion at the cellular level, which were corroborated with appropriate changes in representative molecular markers. Down regulation or ectopic expression of either E-cadherin or PKD1 significantly increased or decreased cell proliferation, motility, and invasion, respectively, and combined down regulation cumulatively influenced the effects. Loss of PKD1 or E-cadherin expression was associated with increased expression of the pro-survival molecular markers survivin, β-catenin, cyclin-D, and c-myc, whereas overexpression of PKD1 and/or E-cadherin resulted in an increase of caspases. The inhibitory effect of PKD1 and E-cadherin on cell proliferation was rescued by coexpression with β-catenin, suggesting that β-catenin mediates the effect of proliferation by PKD1 and E-cadherin. This study establishes the functional significance of combined dysregulation of PKD1 and E-cadherin in PC and that their effect on cell growth is mediated by β-catenin.

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Section: Discussionmentioning

confidence: 99%

β‐catenin mediates alteration in cell proliferation, motility and invasion of prostate cancer cells by differential expression of E‐cadherin and protein kinase D1

Syed

Mak

et al. 2007

J of Cellular Biochemistry

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“…A similar finding was also reported by other 2 groups; Kubota et al 14 showed the up-regulation of p21 by PC-SPES by using western blot analysis, whereas Nelson and coworkers demonstrated induction of the p21 gene using high-density microarray assays as well as northern blot analysis. 18 These results are mechanistically compatible with the observed changes in cell regulatory protein expression, measured by immunoblot analysis (Fig.…”

Section: Discussionmentioning

confidence: 96%

“…The ability of PC-SPES to inhibit LNCaP cell growth has been attributed to G 1 block. 14 A key protein for controlling this checkpoint of the cell cycle is the retinoblastoma gene product Rb. 20 In an attempt to relate cell cycle progression with growth control following PC-SPES treatment, we performed western blot analysis to assess changes in the expression of PCNA and Rb.…”

Section: Control Of Lncap Proliferation and Psa Expression By Pc-spesmentioning

confidence: 99%

“…10,11,[14][15][16][17] In vitro studies from this and other laboratories have demonstrated that PC-SPES elicits a multitude of biological responses contributing to its anti-prostatic activities. 6,10,11,14,[16][17][18] These include disruption of cell cycle control and decreased expression of proliferating cellular nuclear antigen (PCNA), induction of apoptosis concomitant with down regulation of bcl-2, and diminution of prostate specific gene expression, exemplified by reduction in the androgen receptor (AR) and PSA levels. The ability of PC-SPES to suppress prostate cancer cell growth is particularly noteworthy and may principally account for its anti-tumor effects; however, how PC-SPES induces cell cycle arrest is not clear.…”

Section: Introductionmentioning

confidence: 99%

“…In this study, we assessed the control of key cell cycle regulatory proteins by PC-SPES. Since PC-SPES blocked G 1 /S progression in LNCaP cells, 14 we focused on cyclins D and E and Rb. As a complementary approach, we also used human cell cycle specific cDNA array to characterize the transcriptional responses of LNCaP prostate cancer cells to PC-SPES and to establish a platform that will permit identification of genes with obligatory or facilitory roles in the PC-SPES mediated cell cycle control.…”

Section: Introductionmentioning

confidence: 99%

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PC-SPES Inhibits Cell Proliferation by Modulating p21, Cyclins D, E and B and Multiple Cell Cycle-Related Genes in Prostate Cancer Cells

Guo²,

Hsieh³

2003

Cell Cycle

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PC-SPES is an herbal mixture, with evidence of clinical efficacy against prostate cancer (CaP), recently attracting tremendous attention. Using immunoblot and cell cycle specific cDNA array analyses, we investigated effects of PC-SPES on LNCaP, a hormonedependent prostate cancer cell line. PC-SPES inhibited expression of cyclins D and E, inhibited Rb phosphorylation, switching it to a G1-to-S inhibitory state. Moreover, cDNA array analysis showed that PC-SPES caused up-regulation of p21 WAF1/CIP1 and decreased expression of cyclin B, Nedd8, cdc2, skp1, PCNA, MAD2L1, cyclin H, CKS2, E2F, Rbx1, MCM2, MCM5, Mpp2, Cullin-Cul4A, Cks1p9 and McM7, which are involved in cell cycle progression. Taken together, our results provide a mechanistic explanation for antiproliferative and antitumor effects of PC-SPES, suggesting that induction of CDK inhibitors and downregulation of cyclins leads to dephosphorylation of Rb and growth arrest.

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Estrogens and anti‐estrogens: Key mediators of prostate carcinogenesis and new therapeutic candidates

2003

J of Cellular Biochemistry

169

130

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Despite the historical use of estrogens in the treatment of prostate cancer (PCa) little is known about their direct biological effects on the prostate, their role in carcinogenesis, and what mechanisms mediate their therapeutic effects on PCa. It is now known that estrogens alone, or in synergism with an androgen, are potent inducers of aberrant growth and neoplastic transformation in the prostate. The mechanisms of estrogen carcinogenicity could be mediated via induction of unscheduled cell proliferation or through metabolic activation of estrogens to genotoxic metabolites. Age-related changes and race-/ethnic-based differences in circulating or locally formed estrogens may explain differential PCa risk among different populations. Loss of expression of estrogen receptor (ER)-beta expression during prostate carcinogenesis and prevention of estrogen-mediated oxidative damage could be exploited in future PCa prevention strategies. Re-expression of ER-beta in metastatic PCa cells raises the possibility of using ER-beta-specific ligands in triggering cell death in these malignant cells. A variety of new estrogenic/anti-estrogenic/selective estrogen receptor modulator (SERM)-like compounds, including 2-methoxyestradiol, genistein, resveratrol, licochalcone, Raloxifene, ICI 182,780, and estramustine are being evaluated for their potential in the next generation of PCa therapies. Increasing numbers of patients self-medicate with herbal formulations such as PC-SPES. Some of these compounds are selective ER-beta ligands, while most of them have minimal interaction with ER-alpha. Although many may inhibit testosterone production by blockade of the hypothalamal-pituitary-testis axis, the most effective agents also exhibit direct cytostatic, cytotoxic, or apoptotic action on PCa cells. Some of them are potent in interfering with tubulin polymerization, blocking angiogenesis and cell motility, suppressing DNA synthesis, and inhibiting specific kinase activities. Further discovery of other compounds with potent apoptotic activities but minimal estrogen action should promote development of a new generation of effective PCa preventive or treatment regimens with few or no side-effects due to estrogenicity. Further advancement of our knowledge of the role of estrogens in prostate carcinogenesis through metabolic activation of estrogens and/or ER-mediated pathways will certainly result in better preventive or therapeutic modalities for PCa.

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PC-SPES: A unique inhibitor of proliferation of prostate cancer cells in vitro and in vivo

Cited by 81 publications

References 35 publications

β‐catenin mediates alteration in cell proliferation, motility and invasion of prostate cancer cells by differential expression of E‐cadherin and protein kinase D1

β‐catenin mediates alteration in cell proliferation, motility and invasion of prostate cancer cells by differential expression of E‐cadherin and protein kinase D1

PC-SPES Inhibits Cell Proliferation by Modulating p21, Cyclins D, E and B and Multiple Cell Cycle-Related Genes in Prostate Cancer Cells

Estrogens and anti‐estrogens: Key mediators of prostate carcinogenesis and new therapeutic candidates

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