Article

Natriuretic Peptide Receptor A as a Novel Anticancer Target

Joy McCann Culverhouse Airway Disease and Nanomedicine Research Center, Allergy and Immunology Division, Department of Internal Medicine, University of South Florida College of Medicine, Tampa, FL 33612, USA.
Cancer Research (Impact Factor: 9.33). 02/2008; 68(1):249-56. DOI: 10.1158/0008-5472.CAN-07-3086
Source: PubMed

ABSTRACT

The receptor for atrial natriuretic peptide (ANP), natriuretic peptide receptor A (NPRA), is expressed in cancer cells, and natriuretic peptides have been implicated in cancers. However, the direct role of NPRA signaling in tumorigenesis remains elusive. Here, we report that NPRA expression and signaling is important for tumor growth. NPRA-deficient mice showed significantly reduced antigen-induced pulmonary inflammation. NPRA deficiency also substantially protected C57BL/6 mice from lung, skin, and ovarian cancers. Furthermore, a nanoparticle-formulated interfering RNA for NPRA attenuated B16 melanoma tumors in mice. Ectopic expression of a plasmid encoding NP73-102, the NH(2)-terminal peptide of the ANP prohormone, which down-regulates NPRA expression, also suppressed lung metastasis of A549 cells in nude mice and tumorigenesis of Line 1 cells in immunocompetent BALB/c mice. The antitumor activity of NP73-102 was in part attributed to apoptosis of tumor cells. Western blot and immunohistochemistry staining indicated that the transcription factor, nuclear factor-kappaB, was inactivated, whereas the level of tumor suppressor retinoblastoma protein was up-regulated in the lungs of NPRA-deficient mice. Furthermore, expression of vascular endothelial growth factor was down-regulated in the lungs of NPRA-deficient mice compared with that in wild-type mice. These results suggest that NPRA is involved in tumor angiogenesis and represents a new target for cancer therapy.

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    • "The receptor for the cardiac hormone atrial natriuretic peptide (ANP), natriuretic peptide receptor A (NPR-A), have been reported to be expressed in lung cancer, prostate cancer, ovarian cancer. NPR-A expression and signaling is important for tumor growth, its deficiency protect C57BL/6 mice from lung, skin, and ovarian cancers, and these result suggest that NPR-A is a new target for cancer therapy [4] [5]. "
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    ABSTRACT: The receptors for the cardiac hormone atrial natriuretic peptide (ANP), natriuretic peptide receptor A (NPR-A), have been reported to be expressed in lung cancer, prostate cancer, ovarian cancer. NPR-A expression and signaling is important for tumor growth, its deficiency protect C57BL/6 mice from lung, skin, and ovarian cancers, and these result suggest that NPR-A is a new target for cancer therapy. Recently, NPR-A has been demonstrated to be expressed in pre-implantation embryos and in ES cells, it has a novel role in the maintenance of self-renewal and pluripotency of ES cells. However, the direct role of NPR-A signaling in gastric cancer remains unclear. NPR-A expression was downregulated by transfection of shRNA. The proliferation of gastric cancer cells was measured by Hoechst 33342 stain. Cell proliferation and invasion were determined via BrdU and transwell assays, respectively. Down-regulation of NPR-A expression by shNPR-A induced apoptosis, inhibited proliferation and invasion in AGS cells. The mechanism of shNPR-A-induced anti-AGS effects was linked to NPR-A-induced expression of KCNQ1, a gene to be overexpressed in AGS and significantly reduced by shNPR-A. Collectively, these results suggest that NPR-A promotes gastric cancer development in part by regulating KCNQ1. Our findings also suggest that NPR-A is a target for gastric cancer therapy.
    Full-text · Article · Oct 2014 · International Journal of Clinical and Experimental Medicine
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    • "Control animals receiving only PBS showed nodules and tumors, whereas the NP73-102-treated group had no tumors. In the BALB/c mice tumor model, those treated with pNP73-102 nanoparticles injected weekly showed significantly reduced tumor burden compared to those treated with PBS or pVAX1 control vector [8]. TUNEL assay, Western blot of the cleavage of caspase 3 substrates, and PARP show that NP73-102 induces apoptosis of A549 adenocarcinoma. "
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    ABSTRACT: The receptor for the cardiac hormone atrial natriuretic peptide (ANP), natriuretic peptide receptor A (NPR-A), has been reported to be expressed in lung cancer, prostate cancer and ovarian cancer. NPR-A expression and signaling is important for tumor growth; its deficiency protects C57BL/6 mice from lung, skin and ovarian cancers. This suggests that NPR-A is a new marker and a new target for cancer therapy. Recently, NPR-A has been demonstrated to be expressed in pre-implantation embryos and in embryonic stem cells, which has a novel role in the maintenance of self-renewal and pluripotency of embryonic stem cells. A nanoparticle-formulated interfering RNA for NPR-A attenuated B16 melanoma tumors in mice. Ectopic expression of a plasmid encoding NP73-102, the NH2-terminal peptide of the ANP prohormone which downregulates NPR-A expression, also suppressed lung metastasis of A549 cells in nude mice and tumorigenesis of Line 1 cells in immunocompetent BALB/c mice. These results suggest that NPR-A is involved in tumorigenesis and a new target for cancer therapy. This review focuses on structure, abnormal functions and carcinogenic mechanisms of NPR-A to investigate its role in tumorigenesis.
    Full-text · Article · Jun 2014 · World Journal of Surgical Oncology
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    • "For example, NPRA was found to be frequently expressed in human prostate cancer (PCa) cells, and downregulation of NPRA induced apoptosis in PCa cells. Furthermore, NPRA deficiency can substantially protect C57BL/6 mice from lung, skin, and ovarian cancers [14]. "
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    ABSTRACT: Background The natriuretic peptide receptor-A (NPRA) has been investigated as a receptor of natriuretic peptides in the cardiovascular system. In this study, however, we analyze the expression status of NPRA and the relationship with tumor invasion in esophageal squamous cell carcinoma (ESCC) for the first time. Methods Western blots were used to examine the expression status of protein in human ESCC cell lines. Then, we used immunohistochemistry to detect the expression of NPRA in 45 ESCC specimens and 40 corresponding nontumor tissues. The clinical data were analyzed through statistical methods. Sh-RNA-NPRA was transfected into Eca109 cells to detect the relationship between NPRA and cell invasion through transwell assays. Results In esophageal squamous cells, the expression of NPRA was strongly detected in the cytoplasm, while undetectable or very weak in the nucleus. The positive rates of NPRA in cancer tissues are significantly higher than that in nontumor tissues (P <0.05). Clinicopathological analyses revealed that increased NPRA expression correlated with differentiation and TNM stage (P <0.05), while it showed no statistically significant association with age, gender, and lymph node metastasis. In analysis of prognosis, we found that highly.Transwell assays showed that NPRA promoted Eca109 cell migration and invasion in vitro and may be involved in MMP2 and MMP9 activation. Conclusions NPRA protein is highly expressed in ESCC tissues and could promote Eca109 cell migration and invasion in vitro.
    Full-text · Article · May 2014 · World Journal of Surgical Oncology
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