Role of procathepsin D activation peptide in prostate cancer growth

Větvička, Václav; Větvičková, Jana; Fusek, Martin

doi:10.1002/1097-0045(20000615)44:1<1::aid-pros1>3.0.co;2-4

Cited by 31 publications

(36 citation statements)

References 30 publications

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“…Breast cancer cells with down-regulated expression of pCD by either antisense gene transfer [187], RNA interference [188] or ribozymes [189] displayed reduced growth in vitro and in vivo. Tumor growth was also inhibited by anti-pCD antibodies in vivo and in vitro [180,183,190,191].…”

Section: Cancer Cell Proliferationmentioning

confidence: 90%

“…The extracellular pH of tumors is moderately acidic [192,193] and the secreted pCD could therefore be converted to the active enzyme in an extracellular milieu. However, we showed that the growth promoting effect of pCD on cancer cells is not inhibited by pepstatin A [180,183]. Recent studies clearly demonstrated that enzymatically inactive pCD mutants stimulate growth of cancer cells in vitro and in vivo in the same manner as wild type pCD [130,194].…”

Section: Cancer Cell Proliferationmentioning

confidence: 98%

“…Since that time, numerous studies clearly demonstrated that pCD secreted from cancer cells serve as an autocrine growth factor for breast [180,181], prostate [182,183], ovarian [184] and lung cancer cells [185,186]. Breast cancer cells with down-regulated expression of pCD by either antisense gene transfer [187], RNA interference [188] or ribozymes [189] displayed reduced growth in vitro and in vivo.…”

Section: Cancer Cell Proliferationmentioning

confidence: 99%

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Cathepsin D—Many functions of one aspartic protease

Beneš

Větvička

Fusek

2008

Critical Reviews in Oncology/Hematology

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540

474

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For years, it has been held that cathepsin D (CD) is involved in rather nonspecific protein degradation in a strongly acidic milieu of lysosomes. Studies with CD knock-out mice revealed that CD is not necessary for embryonal development but it is indispensable for postnatal tissue homeostasis. Mutation that abolishes CD enzymatic activity causes neuronal ceroid lipofuscinosis (NCL) characterized by severe neurodegeneration, developmental regression, visual loss and epilepsy in both animals and humans.In the last decade, however, an increasing number of studies demonstrated that enzymatic function of CD is not restricted solely to acidic milieu of lysosomes with important consequences in regulation of apoptosis. In addition to CD enzymatic activity, it has been shown that apoptosis is also regulated by catalytically inactive mutants of CD which suggests that CD interacts with other important molecules and influences cell signaling.Moreover, procathepsin D, secreted from cancer cells, acts as a mitogen on both cancer and stromal cells and stimulates their pro-invasive and pro-metastatic properties. Numerous studies found that pCD/CD level represents an independent prognostic factor in a variety of cancers and is therefore considered to be a potential target of anti-cancer therapy.Studies dealing with functions of cathepsin D are complicated by the fact that there are several simultaneous forms of CD in a cell -pCD, intermediate enzymatically active CD and mature heavy and light chain CD. It became evident that these forms may differently regulate the above mentioned processes.In this article, we review the possible functions of CD and its various forms in cells and organisms during physiological and pathological conditions.

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Section: Cancer Cell Proliferationmentioning

confidence: 90%

Section: Cancer Cell Proliferationmentioning

confidence: 98%

Section: Cancer Cell Proliferationmentioning

confidence: 99%

See 1 more Smart Citation

Cathepsin D—Many functions of one aspartic protease

Beneš

Větvička

Fusek

2008

Critical Reviews in Oncology/Hematology

Self Cite

540

474

View full text Add to dashboard Cite

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“…No additional similarity was considered to be significant. Subsequent experiments demonstrated that prostate cancer cells PC3, DU145, and LNCaP 38,57 and ovarian cancer cells UL-1 and SKOV-3 58 are similarly sensitive to the pCD treatment. Furthermore, this mitogenic activity was blocked by antibodies to APpCD.…”

Section: Cancer Gene Therapymentioning

confidence: 99%

Procathepsin D in breast cancer: What do we know? Effects of ribozymes and other inhibitors

2002

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Procathepsin D (pCD) is a major secreted glycoprotein in some human breast and other cancer cell lines. Several groups proposed that pCD served as a growth factor for these cell lines. Secreted pCD has been demonstrated in tissue section, tissue culture supernatants, carcinoma cytosols, and nipple aspirates. Moreover, several clinical studies suggested a potential role for this molecule in metastasis because its concentration in primary tumors correlated with an increased incidence of tumor metastases. In this paper, the effects of pCD were evaluated by proliferation in vitro and by mouse studies in vivo. Subsequent flow cytometry experiments showed the specificity of pCD binding to cancer cells. Cell cultivation showed that addition of either pCD or its activation peptide stimulates growth of cancer cells. These effects can be inhibited both in vitro and in vivo by anti-pCD antibodies. In addition, production of pCD can be inhibited by specifically designed ribozymes. This paper is focused on mitogenic effects of pCD, which seem to involve interaction of the activation peptide with as yet unidentified receptor. Different mechanisms by which pCD could promote development and spread of cancer cells are discussed.

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“…Such aberrant secretion is present in many cancer types (Liaudet-Coopman et al, 2006), in a number of different glycoforms (Capony et al, 1989), which may account for the cluster of spots represented by the protein in this study. Pro-cathepsin D is known to function as a mitogen, acting entirely independently of its proteolytic activity (Vetvicka et al, 2000;Vashishta et al, 2006), although the mechanism mediating these effects is yet to be understood. On the basis of characterisation of the reactivity of the antibodies used in our ELISA, it is likely that the assay measures both precursor and mature forms.…”

Section: Discussionmentioning

confidence: 99%

Pre-operative urinary cathepsin D is associated with survival in patients with renal cell carcinoma

et al. 2009

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BACKGROUND: No circulating markers are routinely used for renal cancer. The objective of this pilot study was to investigate whether conditioned media (CM) from renal cancer cell lines contains potential biomarkers that, when measured in clinical fluids, have diagnostic or prognostic utility. METHODS: Comparative 2D PAGE profiling of CM from renal cell carcinoma (RCC) and normal renal cultures identified cathepsin D that was subsequently validated in urine samples from 239 patients and healthy and benign disease subjects. RESULTS: Urinary cathepsin D was found to be significantly associated with overall (OS) (hazard ratio, HR, 1.33, 95%CI [1.09 -1.63], P ¼ 0.005) and cancer-specific survival (HR 1.36, 95%CI [1.07 -1.74], P ¼ 0.013) in RCC patients on univariate analysis. An optimal cut point (211 ng ml À1 mmolCr À1 ) around which to stratify patients by OS was determined. Five-year OS equal to/above and below this value was 47.0% (95%CI 35.4%, 62.4%) and 60.9% (48.8%, 76.0%), respectively. On multivariable analysis using pre-operative variables, cathepsin D showed some evidence of independent prognostic value for OS (likelihood ratio test P-value ¼ 0.056) although requiring further validation in larger patient numbers with sufficient statistical power to determine independent significance. CONCLUSION: These data establish an important proof of principle and show the potential of proteomics-based studies. Cathepsin D may be of value as a pre-operative urinary biomarker for RCC, alone or in combination.

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Role of procathepsin D activation peptide in prostate cancer growth

Cited by 31 publications

References 30 publications

Cathepsin D—Many functions of one aspartic protease

Cathepsin D—Many functions of one aspartic protease

Procathepsin D in breast cancer: What do we know? Effects of ribozymes and other inhibitors

Pre-operative urinary cathepsin D is associated with survival in patients with renal cell carcinoma

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