Vitamin D May Reduce Prostate Cancer Metastasis by Several Mechanisms Including Blocking Stat3
The recent article by Abdulghani and colleagues1 in reporting that Stat3 promotes metastatic progression of prostate cancer opens the door to new approaches to fight this cancer. This letter proposes that vitamin D might be beneficial in reducing the risk of prostate cancer mortality by inhibiting the action of Stat3.
[Note from megaSun New Zealand to explain Stat3:The Stat3 gene's official name of this gene is "signal transducer and activator of transcription 3" (acute-phase response factor). The STAT3 protein has been found to be overactive in several common forms of cancer. For example, abnormal STAT3 protein activation has been identified in many cancers of the breast, prostate, and pancreas, as well as cancers of blood-forming cells (leukemia and lymphoma). Where is the STAT3 gene located? Cytogenetic Location: 17q21.31].
Solar UVB and vitamin D have long been hypothesized to reduce the risk of prostate cancer mortality.2 Whereas solar UVB is correlated with increased survival for those diagnosed with prostate cancer,3 serum 25-hydroxyvitamin D (calcidiol) measured 1 to 8 years before detection of prostate cancer generally does not show a significant correlation with incidence, although higher calcidiol levels are significantly correlated with more aggressive forms of prostate cancer.4 These findings suggest that vitamin D is more effective at reducing metastasis than progression of prostate cancer. Similar results have been found for many other cancers, based on the dependence of cancer survival on season in Norway5 and that solar UVB is more highly correlated with cancer mortality rates than cancer incidence rates for many cancers in the United States.6
Laboratory studies with the hormonal metabolite of vitamin D, 1,25-dihydroxyvitamin D (calcidiol), indicate that calcidiol might be effective in combating prostate cancer. One study found that calcitriol inhibits the synthesis and actions of pro-inflammatory prostaglandins by three mechanisms.7 Another study identified calcitriol as a negative regulator of androgen inactivation in prostate cancer LNCaP cells.8 With respect to Stat3, it was reported that in vitro treatment of activated T cells with calcidiol inhibited the interleukin-12-induced tyrosine phosphorylation of Stat3.9Several studies have reported that inhibiting phosphorylation of Stat3 impairs the role of Stat3 in carcinogenesis. In one study, decreased phosphorylation decreased induction of Stat3 target genes and increased apoptosis10; in another, decreased phosphorylation decreased transforming growth factor-β-mediated invasion and metastasis in pancreatic cancer cells.11
To date the beneficial role of calcidiol in reducing the risk of death from prostate cancer3 is stronger than that of calcitriol.12 Prostate cells express vitamin D-25-hydroxylase (25-OHase) and can convert calcidiol to calcitriol.13 Thus, making sure that those diagnosed with prostate cancer have high calcidiol levels might be appropriate.
In conclusion, the findings by Abdulghani and colleagues1 might help to explain the benefit of vitamin D in increasing the survival rate for prostate cancer, and the findings by Muthian and colleagues9 might help lead to a therapeutic way to reduce the role of Stat3 in leading to metastasis of prostate cancer.
William B. Grant
Sunlight, Nutrition, and Health Research Center, San Francisco, CA
1. Abdulghani J, Gu L, Dagvadorj A, Lutz J, Leiby B, Bonuccelli G, Lisanti MP, Zellweger T, Alanen K, Mirtti T, Visakorpi T, Bubendorf L, Nevalainen MT. Stat3 promotes metastatic progression of prostate cancer. Am J Pathol. 2008;172:1717-1728. [PMC free article] [PubMed]
2. Schwartz GG, Hulka BS. Is vitamin D deficiency a risk factor for prostate cancer? (Hypothesis).Anticancer Res. 1990;10:1307-1311. [PubMed]
3. Lagunova Z, Porojnicu AC, Dahlback A, Berg JP, Beer TM, Moan J. Prostate cancer survival is dependent on season of diagnosis. Prostate. 2007;67:1362-1370. [PubMed]
4. Ahn J, Peters U, Albanes D, Purdue MP, Abnet CC, Chatterjee N, Horst RL, Hollis BW, Huang WY, Shikany JM, Hayes RB. Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial Project Team: serum vitamin D concentration and prostate cancer risk: a nested case-control study. J Natl Cancer Inst. 2008;100:796-804. [PubMed]
5. Porojnicu AC, Dahlback A, Moan J. Sun exposure and cancer survival in Norway: changes in the risk of death with season of diagnosis and latitude. Adv Exp Med Biol. 2008;624:43-54.[PubMed]
6. Boscoe FP, Schymura MJ. Solar ultraviolet-B exposure and cancer incidence and mortality in the United States, 1993-2002. BMC Cancer. 2006;6:264. [PMC free article] [PubMed]
7. Krishnan AV, Moreno J, Nonn L, Swami S, Peehl DM, Feldman D. Calcitriol as a chemopreventive and therapeutic agent in prostate cancer: role of anti-inflammatory activity. J Bone Miner Res. 2007;22(Suppl 2):V74-V80. [PubMed]
8. Kaeding J, Bélanger J, Caron P, Verreault M, Bélanger A, Barbier O. Calcitrol (1alpha,25-dihydroxyvitamin D3) inhibits androgen glucuronidation in prostate cancer cells. Mol Cancer Ther. 2008;7:380-390. [PubMed]
9. Muthian G, Raikwar HP, Rajasingh J, Bright JJ. 1,25 Dihydroxyvitamin-D3 modulates JAK-STAT pathway in IL-12/IFNgamma axis leading to Th1 response in experimental allergic encephalomyelitis. J Neurosci Res. 2006;83:1299-1309. [PubMed]
10. Herrmann A, Vogt M, Mönnigmann M, Clahsen T, Sommer U, Haan S, Poli V, Heinrich PC, Müller-Newen G. Nucleocytoplasmic shuttling of persistently activated STAT3. J Cell Sci.2007;120:3249-3261. [PubMed]
11. Zhao S, Venkatasubbarao K, Lazor JW, Sperry J, Jin C, Cao L, Freeman JW. Inhibition of STAT3 Tyr705 phosphorylation by Smad4 suppresses transforming growth factor beta-mediated invasion and metastasis in pancreatic cancer cells. Cancer Res. 2008;68:4221-4228. [PubMed]
12. Beer TM, Ryan CW, Venner PM, Petrylak DP, Chatta GS, Ruether JD, Redfern CH, Fehrenbacher L, Saleh MN, Waterhouse DM, Carducci MA, Vicario D, Dreicer R, Higano CS, Ahmann FR, Chi KN, Henner WD, Arroyo A, Clow FW. ASCENT Investigators: double-blinded randomized study of high-dose calcitriol plus docetaxel compared with placebo plus docetaxel in androgen-independent prostate cancer: a report from the ASCENT Investigators.J Clin Oncol. 2007;25:669-674. [PubMed]
13. Flanagan JN, Young MV, Persons KS, Wang L, Mathieu JS, Whitlatch LW, Holick MF, Chen TC. Vitamin D metabolism in human prostate cells: implications for prostate cancer chemoprevention by vitamin D. Anticancer Res. 2006;26:2567-2572. [PubMed]
Article from The American Journal of Pathology are provided by courtesy of American Society for Investigative Pathology