Elevated Cyclic AMP Levels Promote BRAF/Pten Mouse Melanoma Growth but PCREB is Negatively Correlated with Human Melanoma Progression

Overview

Journal Cancer Lett

Specialty Oncology

Date 2017 Nov 29

PMID 29179997

Citations 7

Authors

Carlos I Rodriguez

Edgardo Castro-Perez

B Jack Longley

Vijayasaradhi Setaluri

Affiliations

Soon will be listed here.

Abstract

Melanocyte development and differentiation are regulated by cAMP, which is produced by the adenylate cyclase (AC) enzyme upon activation of the melanocortin-1-receptor (MC1R). Individuals carrying single amino acid substitution variants of MC1R have impaired cAMP signaling and higher risk of melanoma. However, the contribution of AC to this risk is not clear. Downstream of AC, the phosphorylated transcription factor, cyclic AMP Responsive Element Binding Protein (pCREB), which is activated by protein kinase A, regulates the expression of several genes including the melanocyte master regulator MITF. The roles of AC and CREB in melanoma development and growth are not well understood. Here, we investigated the effect of topical application of AC inhibitor on Braf/Pten mouse melanoma development. We show that AC inhibitor delays melanoma growth independent of MAPK pathway activity and melanin content. Next, employing a primary melanoma tissue microarray and quantitative immunohistochemistry, we show that pCREB levels are positively correlated with the proliferative status of melanoma, but low pCREB expression is associated with tumor aggressiveness and metastatic recurrence. These data suggest that low cAMP signaling inhibits tumor growth but is a predictor of melanoma aggressiveness.

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References

Carreira S, Goodall J, Denat L, Rodriguez M, Nuciforo P, Hoek K . Mitf regulation of Dia1 controls melanoma proliferation and invasiveness. Genes Dev. 2006; 20(24):3426-39. PMC: 1698449. DOI: 10.1101/gad.406406. View

Li H, Kim S, Savkovic V, Jin S, Choi Y, Yun S . Expression of soluble adenylyl cyclase in acral melanomas. Clin Exp Dermatol. 2015; 41(4):425-9. DOI: 10.1111/ced.12730. View

Box N, Duffy D, IRVING R, Russell A, Chen W, Griffyths L . Melanocortin-1 receptor genotype is a risk factor for basal and squamous cell carcinoma. J Invest Dermatol. 2001; 116(2):224-9. DOI: 10.1046/j.1523-1747.2001.01224.x. View

Magro C, Crowson A, Desman G, Zippin J . Soluble adenylyl cyclase antibody profile as a diagnostic adjunct in the assessment of pigmented lesions. Arch Dermatol. 2011; 148(3):335-44. PMC: 3387488. DOI: 10.1001/archdermatol.2011.338. View

Mitra D, Luo X, Morgan A, Wang J, Hoang M, Lo J . An ultraviolet-radiation-independent pathway to melanoma carcinogenesis in the red hair/fair skin background. Nature. 2012; 491(7424):449-53. PMC: 3521494. DOI: 10.1038/nature11624. View

Desman G, Waintraub C, Zippin J . Investigation of cAMP microdomains as a path to novel cancer diagnostics. Biochim Biophys Acta. 2014; 1842(12 Pt B):2636-45. PMC: 4281520. DOI: 10.1016/j.bbadis.2014.08.016. View

QUEVEDO Jr W, Fleischmann R . Developmental biology of mammalian melanocytes. J Invest Dermatol. 1980; 75(1):116-20. DOI: 10.1111/1523-1747.ep12521335. View

Rodriguez C, Setaluri V . Cyclic AMP (cAMP) signaling in melanocytes and melanoma. Arch Biochem Biophys. 2014; 563:22-7. DOI: 10.1016/j.abb.2014.07.003. View

Yoshida H, Kunisada T, Grimm T, Nishimura E, Nishioka E, Nishikawa S . Review: melanocyte migration and survival controlled by SCF/c-kit expression. J Investig Dermatol Symp Proc. 2002; 6(1):1-5. DOI: 10.1046/j.0022-202x.2001.00006.x. View

10.

Li C, Xie J, Lu Z, Chen C, Yin Y, Zhan R . ADCY7 supports development of acute myeloid leukemia. Biochem Biophys Res Commun. 2015; 465(1):47-52. PMC: 4554980. DOI: 10.1016/j.bbrc.2015.07.123. View

11.

Magro C, Yang S, Zippin J, Zembowicz A . Expression of soluble adenylyl cyclase in lentigo maligna: use of immunohistochemistry with anti-soluble adenylyl cyclase antibody (R21) in diagnosis of lentigo maligna and assessment of margins. Arch Pathol Lab Med. 2012; 136(12):1558-64. PMC: 3732207. DOI: 10.5858/arpa.2011-0617-OA. View

12.

Pierre S, Eschenhagen T, Geisslinger G, Scholich K . Capturing adenylyl cyclases as potential drug targets. Nat Rev Drug Discov. 2009; 8(4):321-35. DOI: 10.1038/nrd2827. View

13.

Dankort D, Curley D, Cartlidge R, Nelson B, Karnezis A, Damsky Jr W . Braf(V600E) cooperates with Pten loss to induce metastatic melanoma. Nat Genet. 2009; 41(5):544-52. PMC: 2705918. DOI: 10.1038/ng.356. View

14.

Shaywitz A, Greenberg M . CREB: a stimulus-induced transcription factor activated by a diverse array of extracellular signals. Annu Rev Biochem. 2000; 68:821-61. DOI: 10.1146/annurev.biochem.68.1.821. View

15.

Fallahi M, Amelio A, Cleveland J, Rounbehler R . CREB targets define the gene expression signature of malignancies having reduced levels of the tumor suppressor tristetraprolin. PLoS One. 2014; 9(12):e115517. PMC: 4277357. DOI: 10.1371/journal.pone.0115517. View

16.

Box N, Wyeth J, OGorman L, Martin N, Sturm R . Characterization of melanocyte stimulating hormone receptor variant alleles in twins with red hair. Hum Mol Genet. 1997; 6(11):1891-7. DOI: 10.1093/hmg/6.11.1891. View

17.

Luisa Kadekaro A, Kanto H, Kavanagh R, Abdel-Malek Z . Significance of the melanocortin 1 receptor in regulating human melanocyte pigmentation, proliferation, and survival. Ann N Y Acad Sci. 2003; 994:359-65. DOI: 10.1111/j.1749-6632.2003.tb03200.x. View

18.

Hong S, Goh S, Lee S, Hwang J, Lee J, Choi I . Upregulation of adenylate cyclase 3 (ADCY3) increases the tumorigenic potential of cells by activating the CREB pathway. Oncotarget. 2013; 4(10):1791-803. PMC: 3858564. DOI: 10.18632/oncotarget.1324. View

19.

Devi S, Kedlaya R, Maddodi N, Bhat K, Weber C, Valdivia H . Calcium homeostasis in human melanocytes: role of transient receptor potential melastatin 1 (TRPM1) and its regulation by ultraviolet light. Am J Physiol Cell Physiol. 2009; 297(3):C679-87. PMC: 2740396. DOI: 10.1152/ajpcell.00092.2009. View

20.

DOrazio J, Nobuhisa T, Cui R, Arya M, Spry M, Wakamatsu K . Topical drug rescue strategy and skin protection based on the role of Mc1r in UV-induced tanning. Nature. 2006; 443(7109):340-4. DOI: 10.1038/nature05098. View