Anticancer Res. 2013 Aug;33(8):3047-52.

Nicotinamide phosphoribosyltransferase and SIRT3 expression are increased in well-differentiated thyroid carcinomas.

Shackelford R, Turbat-Herrera, E, Hirsh S, Henry K, Abdel-Mageed A, Kandil E, Coppola D.

12902 Magnolia Drive, Tampa, FL, USA. Domenico.Coppola@moffitt.org

 

ABSTRACT

Nicotinamide phosphoribosyltransferase (NAMPT) catalyzes the rate-limiting step of nicotinamide adenine dinucleotide (NAD+) synthesis. NAMPT expression promotes angiogenesis, DNA synthesis, cell growth and survival, and mitochondrial biogenesis and function. Sirtuin-3 (SIRT3) is an NAD+-dependent deacetylase which functions in conjunction with mitochondrial NAMPT to promote cell survival following genotoxic stress. NAMPT expression is increased in several human malignancies, while SIRT3 levels are increased in some malignancies and suppressed in others. Based on this, we hypothesized that NAMPT and SIRT3 expression might be increased in well-differentiated thyroid carcinomas (TCs), follicular carcinomas (FC) and papillary thyroid carcinomas (PTC). Immunohistochemical analysis for NAMPT and SIRT3 staining was performed on these tumors using tissue microarrays. NAMPT and SIRT3 expression was low in benign thyroid tissues, moderately increased in FC, and more highly expressed in PTC. Specifically we observed both NAMPT and SIRT3 to be highly expressed in well-differentiated TCs. The data suggest that mitochondrial alterations play a role in the development and maintenance of well-differentiated TC. Since an effective pharmacological NAMPT inhibitor is currently in clinical use, further studies of NAMPT overexpression in well-differentiated TCs may be useful in selecting patients for NAMPT inhibitor therapy, particularly for metastatic well-differentiated thyroid carcinomas refractory to other treatments.

KEYWORDS: Follicular carcinoma, NAD+, SIRT3, nicotinamide phosphoribosyltransferase, papillary carcinoma

PMID: 23898059

 

SUPPLEMENT

The study by Shackelford et al. focused on the increased expression of Nampt and SirT3 in well-differentiated thyroid carcinomas. Intracellular Nampt is overexpressed in nearly twenty different human malignancies (1). Within cells Nampt catalyses NAD+ synthesis by transferring the phosphoribosyl group of 5-phosporibosyl-1-pyrophosphate to nicotinamide, forming nicotinamide mononucleotide (NMN). NAD+ synthesis is completed by NMN adenylyltransferase, which converts NMN into NAD (2). Nampt catalytic activity is ~46-fold lower than that of Nmnat, so small changes in Nampt protein levels, but not Nmnat levels, profoundly effects NAD+ metabolism and NAD-dependent events (2,3). Increased NAD+ is known to promote malignant progression via increasing the activities of SirT1, CD38, CtBP1 and 2, and PARP-1. Each of these proteins function by degrading NAD+ into an ADP-ribose moiety and NAM. Thus, high Nampt levels are required to synthesize the NAD+ needed for the malignancy-promoting actions of these proteins. SirT1 activity attenuates p53, PTEN, and retinoblastoma activities, stabilizes N-Myc, and promotes the epithelial to mesenchymal transition, while increasing cell migration. CtBP1 and 2 activities promote invasive behaviors in malignant cells, while suppressing apoptosis and several tumor suppressor genes. PARP-1 is overexpressed in many malignancies and its inhibition lowers cancer cell viability. CD38 regulates cell adhesion, calcium signaling, and signal transduction. Its role in cancer is poorly understood (Figure 1, for review 1).

The function of SirT3 in cancer is poorly understood. SirT3 is a mitochondrial NAD+-dependent histone deacetylase that exerts anti-cancer effects by destabilizing HIF-1a and promoting mitochondrial function and cell survival following genotoxin exposure. It also promotes carcinogenesis by attenuating p53 function and promoting metastasis (4,5). In most studies SirT3 expression is cytoplasmic in benign tissue and is suppressed in malignancy (4-6). For example, Yang et al. found SirT3 cytoplasmic expression was suppressed in gastric cancer (6). We obtained the same results examining SirT3 in this malignancy (unpublished data). Our finding that SirT3 expression is increased in both the cytoplasm and nuclei of well-differentiated thyroid carcinomas indicates that: 1), SirT3 expression may be increased in malignancy, and 2) SirT3 expression can be nuclear and associated with malignancy.

 

Figure 1. Increased intracellular Nampt increases cellular NAD+ concentrations, increasing the activities of PARP-1, CD38, SirT1, and CtBP1 and 2, promoting malignancy (modified from 1). This present study indicates that SirT3 overexpression may also play a role in promoting malignancy in well-differentiated thyroid carcinoma.

 

REFERENCES

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2. Rongvaux A, Shea RJ, Mulks MH, Gigot D, Urbain J, Leo O, Andris F. Pre-B-cell colony-enhancing factor, whose expression is up-regulated in activated lymphocytes, is a nicotinamide phosphoribosyltransferase, a cytosolic enzyme involved in NAD biosynthesis. Eur J Immunol. 2002;32:3225-34.

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4. Alhazzazi TY, Kamarajan P, Verdin E, Kapila YL. SIRT3 and cancer: tumor promoter or suppressor? Biochim Biophys Acta. 2011;1816:80-8.

5. Bell EL, Emerling BM, Ricoult SJ, Guarente L. SirT3 suppresses hypoxia inducible factor 1α and tumor growth by inhibiting mitochondrial ROS production. Oncogene. 2011;30:2986-96.

6. Yang B, Fu X, Shao L, Ding Y, Zeng D. Aberrant expression of SIRT3 is conversely correlated with the progression and prognosis of human gastric cancer. Biochem Biophys Res Commun. 2014;443:156-60.

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