Prolidase-dependent regulation of TGF c and TGF β receptor expressions in human skin fibroblasts

Surażyński, Arkadiusz; Miltyk, Wojciech; Prokop, Izabela; Pałka, Jerzy

doi:10.1016/j.ejphar.2010.09.034

Cited by 30 publications

(27 citation statements)

References 30 publications

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“…Second, rhPEPD, rather than rhPEPD G278D , stimulates HIF-1α and its downstream targets (VEGF, GLUT-1) in the tumor tissues via its dipeptidase activity. PEPD was also shown to stimulate TGFβ and its receptor via its dipeptidase function (Surazynski et al, 2010). The stimulating effect of rhPEPD on the prosurvival factors mentioned above likely attenuates its antitumor activity.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of ERBB2-overexpressing Tumors by Recombinant Human Prolidase and Its Enzymatically Inactive Mutant

Yang

Bhattacharya

et al. 2015

EBioMedicine

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ERBB2 is an oncogenic receptor tyrosine kinase overexpressed in a subset of human breast cancer and other cancers. We recently found that human prolidase (PEPD), a dipeptidase, is a high affinity ERBB2 ligand and cross-links two ERBB2 monomers. Here, we show that recombinant human PEPD (rhPEPD) strongly inhibits ERBB2-overexpressing tumors in mice, whereas it does not impact tumors without ERBB2 overexpression. rhPEPD causes ERBB2 depletion, disrupts oncogenic signaling orchestrated by ERBB2 homodimers and heterodimers, and induces apoptosis. The impact of enzymatically-inactive mutant rhPEPDG278D on ERBB2 is indistinguishable from that of rhPEPD, but rhPEPDG278D is superior to rhPEPD for tumor inhibition. The enzymatic function of rhPEPD stimulates HIF-1α and other pro-survival factors in tumors, which likely attenuates its antitumor activity. rhPEPDG278D is also attractive in that it may not interfere with the physiologic function of endogenous PEPD in normal cells. Collectively, we have identified a human protein as an inhibitory ERBB2 ligand that inhibits ERBB2-overexpressing tumors in vivo. Several anti-ERBB2 agents are on the market but are hampered by drug resistance and high drug cost. rhPEPDG278D may synergize with these agents and may also be highly cost-effective, since it targets ERBB2 with a different mechanism and can be produced in bacteria.

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Section: Discussionmentioning

confidence: 99%

Inhibition of ERBB2-overexpressing Tumors by Recombinant Human Prolidase and Its Enzymatically Inactive Mutant

Yang

Bhattacharya

et al. 2015

EBioMedicine

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“…Proline and its metabolism play an important role in the proper functioning of the cell [4]. Proline is known to act as a stress signalling molecule in mitochondria [11, 22, 25] and cytoplasm [4, 7, 23, 24]. Proline bearing reducing potential must be converted in mitochondria to P5C by PRODH/POX for regeneration of oxidizing potential.…”

Section: Discussionmentioning

confidence: 99%

Functional Consequences of Intracellular Proline Levels Manipulation Affecting PRODH/POX–Dependent Pro-Apoptotic Pathways in a Novel in Vitro Cell Culture Model

Zaręba

Surażyński

Chruściel

et al. 2017

Cell Physiol Biochem

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Background/Aims: The effect of impaired intracellular proline availability for proline dehydrogenase/proline oxidase (PRODH/POX)-dependent apoptosis was studied. Methods: We generated a constitutively knocked-down PRODH/POX MCF-7 breast cancer cell line (MCF-7^shPRODH/POX) as a model to analyze the functional consequences of impaired intracellular proline levels. We have used inhibitor of proline utilization in collagen biosynthesis, 2-metoxyestradiol (MOE), inhibitor of prolidase that generate proline, rapamycin (Rap) and glycyl-proline (GlyPro), substrate for prolidase. Collagen and DNA biosynthesis were evaluated by radiometric assays. Cell viability was determined using Nucleo-Counter NC-3000. The activity of prolidase was determined by colorimetric assay. Expression of proteins was assessed by Western blot and immunofluorescence bioimaging. Concentration of proline was analyzed by liquid chromatography with mass spectrometry. Results: PRODH/POX knockdown decreased DNA and collagen biosynthesis, whereas increased prolidase activity and intracellular proline level in MCF-7^shPRODH/POX cells. All studied compounds decreased cell viability in MCF-7 and MCF-7^shPRODH/POX cells. DNA biosynthesis was similarly inhibited by Rap and MOE in both cell lines, but GlyPro inhibited the process only in MCF-7^shPRODH/POX and MOE+GlyPro only in MCF-7 cells. All the compounds inhibited collagen biosynthesis, increased prolidase activity and cytoplasmic proline level in MCF-7^shPRODH/POX cells and contributed to the induction of pro-survival mode only in MCF-7^shPRODH/POX cells. In contrast, all studied compounds upregulated expression of pro-apoptotic protein only in MCF-7 cells. Conclusion: PRODH/POX was confirmed as a driver of apoptosis and proved the eligibility of MCF-7^shPRODH/POX cell line as a highly effective model to elucidate the different mechanisms underlying proline utilization or generation in PRODH/POX-dependent pro-apoptotic pathways.

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“…Several reports suggest that prolidase through regulation of expression of growth factors and transcription factors, e.g. vascular endothelial growth factor (VEGF), hypoxia inducible factor 1α (HIF-1 α), transforming growth factor β (TGF-β) [18][19][20] may be important in many physiologic and pathologic processes like: wound healing, inflammation and angiogenesis. The most representative study demonstrated the role of products of prolidase activity, proline or hydroxyproline in regulation of HIF-1 α degradation.…”

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confidence: 99%

The effect of prolactin and estrogen cross-talk on prolidase– dependent signaling in MCF-7 cells

Surażyński¹,

Miltyk²,

Wołczyński³

et al. 2013

neo

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Estrogen and prolactin play important role in mammary carcinogenesis. The present study was undertaken to evaluate the effect of prolactin and estrogen cross-talk on HIF-1 α level and expression of some HIF-1 α -dependent signaling proteins. Since up-regulation of prolidase activity inhibits HIF-1 α degradation, the enzyme was considered as an interface of estrogen/prolactin signaling. The experiments were performed on MCF-7 cells cultured with prolactin in the presence or absence of estradiol. It was found that in the presence of estradiol, prolactin inhibits prolidase activity and its down-stream signaling proteins: HIF-1α, mTOR, AKT and MAPK p-38, while in the absence of estradiol, an opposite effect was observed. These results suggest that prolactin/estrogen cross-talk exert beneficial effect on prolidase-dependent down regulation of HIF-1α. It suggests that dual action of prolactin and estrogen may be considered as a strategy in therapy of breast cancer. Key words: prolactin, estrogen, HIF-1 α, MCF-7, prolidase, cross-talkThe role of estrogen and their receptors in the promotion and development of breast cancer is well documented by epidemiological data and the therapeutical efficacy of antiestrogen therapy [1]. Similarly, it was shown that prolactin (PRL) also may play an important role in mammary carcinogenesis. PRL is a hormone synthesized as a 23-kDa peptide by the anterior pituitary gland, however it can be produced also locally by the tumor. PRL receptor (PRL-R) is overexpressed in 70-95% of primary breast tumors compared to normal adjacent tissue [2,3,4,5] Prospective epidemiological studies have correlated circulating PRL levels with risk for estrogen receptor-alpha (ERα)-positive breast cancer in pre-and post-menopausal women [6]. However up to now the mechanism of prolactin action in breast cancer is not clear.More direct evidence was obtained with estrogen receptor (ER) positive breast cancer cell lines in which estrogens were found to stimulate the proliferation of these cells both in culture [7] and in nude mice [8]. However, ER positive tumor cells are poorly metastatic compared to ER negative ones [9] and more responsive to antiestrogens [10]. It may suggest a regulatory role of estrogens in breast cancer cell metastasis.The integrity of the extracellular matrix (ECM) is of critical importance for the maintenance of normal tissue. The interaction between cells and ECM proteins, e.g. collagen, can regulate cellular gene expression, differentiation, growth and plays an important role in tumorigenicity and invasiveness [11,12].Estrogens are well known stimulators of collagen biosynthesis and cell growth in several cell types [13][14][15]. Cell locomotion requires extensive degradation of ECM components, including collagens [16]. Although extracellular metalloproteinases initiate the breakdown of collagen, the final step of its degradation is mediated by prolidase.Prolidase (E.C.3.4.13.9) is the enzyme that catalyzes the final step in ECM degradation by releasing proline or hydroxyproline from th...

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Prolidase-dependent regulation of TGF c and TGF β receptor expressions in human skin fibroblasts

Cited by 30 publications

References 30 publications

Inhibition of ERBB2-overexpressing Tumors by Recombinant Human Prolidase and Its Enzymatically Inactive Mutant

Inhibition of ERBB2-overexpressing Tumors by Recombinant Human Prolidase and Its Enzymatically Inactive Mutant

Functional Consequences of Intracellular Proline Levels Manipulation Affecting PRODH/POX–Dependent Pro-Apoptotic Pathways in a Novel in Vitro Cell Culture Model

The effect of prolactin and estrogen cross-talk on prolidase– dependent signaling in MCF-7 cells

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