Prolylcarboxypeptidase Regulates Proliferation, Autophagy, and Resistance to 4-Hydroxytamoxifen-induced Cytotoxicity in Estrogen Receptor-positive Breast Cancer Cells

Duan, Lei; Motchoulski, Natalia; Danzer, Brian; Davidovich, Irina; Shariat‐Madar, Zia; Levenson, Victor

doi:10.1074/jbc.m110.143271

Cited by 38 publications

(49 citation statements)

References 41 publications

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“…The mechanism by which PRCP deletion prevents liver steatosis is unknown. Several reports have suggested that PRCP, which is expressed in a variety of peripheral organs, plays roles in hypertension, immune response, and angiogenesis (2,7,16,18,22). Thus, we cannot exclude the possibility that the phenotype observed in the liver of these mice is due to its direct effect on other substrates of PRCP in the liver and not via the ␣-MSH signaling in the central nervous system.…”

Section: Discussionmentioning

confidence: 68%

Deletion of prolyl carboxypeptidase attenuates the metabolic effects of diet-induced obesity

Jeong

Szabó

Raso

et al. 2012

American Journal of Physiology-Endocrinology and Metabolism

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Jeong JK, Szabo G, Raso GM, Meli R, Diano S. Deletion of prolyl carboxypeptidase attenuates the metabolic effects of diet-induced obesity. Am J Physiol Endocrinol Metab 302: E1502-E1510, 2012. First published March 27, 2012 doi:10.1152/ajpendo.00544.2011.-␣-Melanocyte-stimulating hormone (␣-MSH) is a critical regulator of energy metabolism. Prolyl carboxypeptidase (PRCP) is an enzyme responsible for its degradation and inactivation. PRCP-null mice (PRCP gt/gt ) showed elevated levels of brain ␣-MSH, reduced food intake, and a leaner phenotype compared with wild-type controls. In addition, they were protected against diet-induced obesity. Here, we show that PRCP gt/gt animals have improved metabolic parameters compared with wild-type controls under a standard chow diet (SD) as well as on a high-fat diet (HFD). Similarly to when they are exposed to SD, PRCP gt/gt mice exposed to HFD for 13 wk showed a leaner phenotype due to decreased fat mass, increased energy expenditure, and locomotor activity. They also showed improved insulin sensitivity and glucose tolerance compared with WT controls and a significant reduction in fasting glucose levels. These improvements occured before changes in body weight and composition were evident, suggesting that the beneficial effect of PRCP ablation is independent of the adiposity levels. In support of a reduced gluconeogenesis, liver PEPCK and G-6-Pase mRNA levels were reduced significantly in PRCP gt/gt compared with WT mice. A significant decrease in liver weight and hepatic triglycerides were also observed in PRCP gt/gt compared with WT mice. Altogether, our data suggest that PRCP is an important regulator of energy and glucose homeostasis since its deletion significantly improves metabolic parameters in mice exposed to both SD and HFD.␣-melanocyte-stimulating hormone; energy metabolism; insulin sensitivity; glucose metabolism A PRECISE CONTROL OF CALORIC INTAKE and energy expenditure is fundamental for the balance of energy homeostasis. In the mammalian brain, a product of the proopiomelanocortin (POMC) gene, ␣-melanocyte-stimulating hormone (␣-MSH) plays a central role in detecting, integrating, and responding to a range of central and peripheral inputs relating to energy metabolism (1,4,13,14,20). The use of genetically altered mouse models has shown the importance of ␣-MSH in the regulation of a broad range of metabolic parameters (9, 17). Mice with ablation of the POMC gene are obese, whereas mice overexpressing ␣-MSH in the brain showed protection against diet-induced obesity with improved glucose homeostasis.We have reported recently a molecular mechanism that is responsible for the inactivation and degradation of ␣-MSH (21). Prolylcarboxypeptidase (PRCP) is a serine protease that cleaves the last amino acid at the COOH terminus of small peptides if proline is the penultimate amino acid. We have shown previously that PRCP is expressed in the lateral hypothalamus, where PRCP-expressing neurons target with their axons the paraventricular nucleus of the hypothalamus, a sit...

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Section: Discussionmentioning

confidence: 68%

Deletion of prolyl carboxypeptidase attenuates the metabolic effects of diet-induced obesity

Jeong

Szabó

Raso

et al. 2012

American Journal of Physiology-Endocrinology and Metabolism

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“…7). 5 μM 4-OHT served as a positive control for autophagy induction [47] and the expected increase in the LC3-II band with a reduction in the LC3-I band was detected in all three ERα + breast cancer cell lines, despite the resistance of LCC2 and LCC9 to treatment with ‘physiological’ levels of 4-OHT, e.g., ~100 nM that would be found in the breast tissue of a patient on oral tamoxifen therapy [48]. We noted that the loss of LCC2 and LCC9 cells in the wells treated with 5 μM 4-OHT was greater than for MCF-7 cells (observational data not shown).…”

Section: Resultsmentioning

confidence: 99%

5-Aza-2-deoxycytidine and trichostatin A increase COUP-TFII expression in antiestrogen-resistant breast cancer cell lines

et al. 2014

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COUP-TFII is reduced in endocrine-resistant breast cancer cells and is negatively associated with tumor grade. Transient re-expression of COUP-TFII restores antiestrogen sensitivity in resistant LCC2 and LCC9 cells and repression of COUP-TFII results in antiestrogen-resistance in MCF-7 endocrine-sensitive cells. We addressed the hypothesis that reduced COUP-TFII expression in endocrine-resistant breast cancer cells results from epigenetic modification. The NR2F2 gene encoding COUP-TFII includes seven CpG islands, including one in the 5′ promoter and one in exon 1. Treatment of LCC2 and LCC9 endocrine-resistant breast cancer cells with 5-aza-2′-deoxycytidine (AZA), a DNA methyltransferase (DNMT) inhibitor, +/– trichostatin A (TSA), a histone deacetylase (HDAC) inhibitor, increased COUP-TFII suggesting that the decrease in COUP-TFII is mediated by epigenetic changes. Methylation-specific PCR (MSP) revealed higher methylation of NR2F2 in the first exon in LCC2 and LCC9 cells compared to MCF-7 cells and AZA reduced this methylation. Translational importance is suggested by Cancer Methylome System (CMS) analysis revealing that breast tumors have increased COUP-TFII (NR2F2) promoter and gene methylation versus normal breast.

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“…28 These findings are consistent with those of Duan et al, who showed that PRCP overexpression increased breast cancer cell proliferation and autophagy, and PRCP depletion decreased both. 22 Duan et al also showed that treatment of MCF7 cells with the S28 protease class inhibitor Z-Pro-Prolinal reduced cell proliferation, suggesting that PRCP's enzymatic activity influenced cell proliferation. 22 Alternatively, we were unable to detect any influence of membrane-formed BK or exogenously added BK, Ang II, or Ang- (1-7), substrates and products of PRCP enzymatic activity on cell proliferation.…”

Section: Discussionmentioning

confidence: 99%

“…22 Duan et al also showed that treatment of MCF7 cells with the S28 protease class inhibitor Z-Pro-Prolinal reduced cell proliferation, suggesting that PRCP's enzymatic activity influenced cell proliferation. 22 Alternatively, we were unable to detect any influence of membrane-formed BK or exogenously added BK, Ang II, or Ang- (1-7), substrates and products of PRCP enzymatic activity on cell proliferation. Because Z-Pro-Prolinal is not specific for PRCP, we determined whether mutagenized cDNA of PRCP at codons for 2 active site amino acids of PRCP would support cell proliferation.…”

Section: Discussionmentioning

confidence: 99%

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Prolylcarboxypeptidase promotes angiogenesis and vascular repair

Adams¹,

Stavrou²,

Fang³

et al. 2013

Blood

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Prolylcarboxypeptidase Regulates Proliferation, Autophagy, and Resistance to 4-Hydroxytamoxifen-induced Cytotoxicity in Estrogen Receptor-positive Breast Cancer Cells

Cited by 38 publications

References 41 publications

Deletion of prolyl carboxypeptidase attenuates the metabolic effects of diet-induced obesity

Deletion of prolyl carboxypeptidase attenuates the metabolic effects of diet-induced obesity

5-Aza-2-deoxycytidine and trichostatin A increase COUP-TFII expression in antiestrogen-resistant breast cancer cell lines

Prolylcarboxypeptidase promotes angiogenesis and vascular repair

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