Androgen metabolism in bone tumors

W.G. Degtiar; N.E. Kushlinskii

Androgen metabolism in bone tumors

W.G. Degtiar¹, N.E. Kushlinskii²

research article Pages: 30-36

¹ Ph.D. (Chem.), Leading Research Scientist, Russian Cancer Research Center of N.N. Blokhin Russian Academy of Medical Sciences (Moscow, Russia)
² Dr.Sc. (Med.), Professor, Russian Cancer Research Center of N.N. Blokhin Russian Academy of Medical Sciences (Moscow, Russia)

Keywords: bone tumors androgens metabolism activity of 5α -R 17β -HSD 3β 3α

Abstract

Measurement of activity of main androgen metabolism enzymes in soluble fraction of bone tumors with different histology.

Activity of 5α-R, 17β-HSD, 3β-HSD and 3α-HSD were measured in soluble fraction of bone tumors of 49 both sex patients with different age.

Activity of 5α-R in soluble fractions of malignant tumors with different histology and benign tumors did not differ reliably. Activity of 17β-HSD in soluble fractions of all bone types was most low than the one for other enzymes but in Ewing tumor activity of 17β-HSD was differ reliably from activity in gigantocell tumor (р=0,01) and osteosarcoma (р=0,03). In all tumors 3α-HSD activity was higher than the one of other enzymes and 3β-HSD activity was higher reliably in Ewing tumors than in chondrosarcoma (р=0,0002) but there were no differences in other tumors.

Activities of main androgen metabolism enzymes in soluble fraction of bone tumors do not differ essentially with elimination of 17β-HSD which activity was essentially lower than other enzymes. In soluble fractions of parostal osteosarcoma activity of all measured enzymes was always lower than in other tumors.

How to cite

Дегтярь В.Г., Кушлинский Н.Е. Метаболизм андрогенов в опухолях костей // Вопросы биологической, медицинской и фармацевтической химии. 2014. № 8. С. 30–36.

References

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Mejnuoring K. Mexanizmy' dejstviya androgenov. M.: Mir. 1976.
Bruchovsky N., Wilson J.D. The conversion of testosterone to 5-alpha-androstan-17-beta-ol-3-one by rat prostate in vivo and in vitro // J. Biol. Chem. 1968. V. 243. P. 2012 - 2021.
Bruchovsky N., Wilson J.D. The intranuclear binding of testosterone and 5-alpha-androstan-17-beta-ol-3-one by rat prostate // J. Biol. Chem. 1968. V. 243. P. 5953 - 5960.
Chang Ch., Yeh Sh., Lee S.O., Chang Ta-min. Androgen Receptor (AR). Pathophysiological Roles in Androgen Related Diseases in Skin, Bone/Muscle, Metabolic Syndrome and Neuron/Immune Systems: Lessons Learned from Mice Lacking AR in Specific Cells // Nuclear Receptor Signaling. 2013. V. 11. P. e001.
Gonzalez-Montelongo M.C., Marin R., Gomez T., Diaz M. Androgens are powerful non-genomic inducers of calcium sensitization in visceral smooth muscle // Steroids. 2010. V. 75. P. 533 - 538.
Kushlinskij N.E., Degtyar' V.G. Metabolizm i mexanizm dejstviya androgenov. M.: RAMN. 2005.
Degtyar' V.G., Kushlinskij N.E. Metabolizm androgenov // Uspexi sovremennoj biologii. 2000. T. 120. S. 48-59.
Kang H.Y., Cho C.L., Huang K.L. et al. Nongenomic androgen activation of phosphatidylinositol 3-kinase/Akt signaling pathway in MC3T3-E1 osteoblasts // J. Bone Miner. Res. 2004. V.19. P. 1181 - 1190.
Kang H.Y., Shyr C.R., Huang C.K. et al. Altered TNSALP expression and phosphate regulation contribute to reduced mineralization in mice lacking androgen receptor// Mol. Cell Biol. 2008. V. 28. P. 7354 - 7367.
Pi M., Abby L. P., Darryl L.Q. GPRC6A Mediates the Non-genomic Effects of Steroids // J. Biol. Chem. 2010. V. 285. P. 39953 ? 39964.
Albright F. The effect of hormones on osteogenesis in man // Recent. Prog. Horm. Res. 1947. V. 1. P. 293-353.
Callewaert F., Boonen S., Vanderschueren D. Sex steroids and the male skeleton: a tale of two hormones // Trends Endocrinol. Metab. 2010. V. 21. P. 89-95.
Foresta C., Ruzza G., Mioni R. Osteoporosis and decline of gonadal function in the elderly male // Hormone Res. 1984. V. 19. P. 18 - 22.
Frenkel B., Hong A., Baniwal S.K. et al. Regulation of adult bone turnover by sex steroids // J. Cell Physiol. 2010. V. 224. P. 305-310.
Gasperino J. Androgenic regulation of bone mass in women // Clin. Orthop. 1995. V. 311. P. 278 - 286.
Vanderschueren D., Venken K., Ophoff J. et al. Clinical Review: Sex steroids and the periosteum-reconsidering the roles of androgens and estrogens in periosteal expansion // J. Clin. Endocrinol. Metab. 2006. V. 91. P. 378 - 382.
Vandenput L., Ohlsson C. Sex steroid metabolism in the regulation of bone health in men // J. Steroid Biochem. Mol. Biol. 2010. V. 121. P. 582 - 588.
Tsai M.Y., Shyr C.R., Kang H.Y. et al. The reduced trabecular bone mass of adult ARKO male mice results from the decreased osteogenic differentiation of bone marrow stroma cells // Biochem. Biophys. Res. Commun. 2011. V. 411. P. 477-482.
Carnevale V., Romagnoli E., Cipriani C. et al. Sex hormones and bone in health males // Arch. Biochem. Biophys. 2010. V. 503. P. 110 - 117.
Sinnesael M., Claessens F., Lauren M. et al. Androgen receptor (AR) in osteocytes is important for the maintenance of male skeletal integrity: evidence from targeted AR disruption in mouse osteocytes // J. Bone Miner. Res. 2012. V. 27. P. 2535 - 2543.
McEwan I.J. Androgen receptor modulators: a marriage of chemistry and biology // Future Med. Chem. 2013. V. 5. P. 1109-1120.
Chiang C., Chiu M., Moore A.J. et al. Mineralization and bone resorption are regulated by the androgen receptor in male mice // J. Bone Miner. Res. 2009. V. 24. P. 621 - 631.
Notini A.J., McManus J.F., Moore A. et al. Osteoblast deletion of exon 3 of the androgen receptor gene results in trabecular bone loss in adult male mice // J. Bone Miner. Res. 2007. V. 22. P. 347 ? 356.
Almeida M., Han L., Martin-Millan M. et al. Skeletal involution by age-associated oxidative stress and its acceleration by loss of sex steroids // J. Biol. Chem. 2007. V. 282. P. 27285 - 27297.
Czerwiec F.S., Liaw J.J., Liu S.B. et al. Absence of androgen transcriptional effects in osteoblastic cells despite presence of androgen receptors // Bone. 1997. V. 21. P. 49 - 56.
Kushlinskij N.E., Bassaly'k L.S., Solov'ev Ju.N. i dr. Polovy'e steroidny'e gormony' i osteogennaya sarkoma. Soobshhenie 1. Giperandrogeniya v patogeneze osteogennoj sarkomy' // Vestnik VONC RAMN. 1991. V. 2. P. 7 - 12.
Sergeev P.V., Chukaev S.A., Gorbatenko E.V., Kushlinskij N.E. Soderzhanie testosterona i aktivnost' fermenta 5α-steroid-NAD(P)Δ4-oksidoreduktazy' v normal'noj kostnoj tkani i zlokachestvenny'x opuxolyax kostej // Byull. e'ksp. biol. med. 1997. T. 24. № 9. S. 305 - 307.
Nakano Y., Morimoto I., Ishida O. et al. The receptor, metabolism and effects of androgen in osteoblastic MC3T3-E1 cells // Bone Mineral. 1994. V. 26. P. 245 - 259.
Ribot C., Fromolliers F. Sex steroids and bone tissue // Ann. Endocrinol. 1995. V. 56. P. 49-55.
Svoboda M., Hamilton G., Thalhammer T. Steroid hormone metabolizing enzymes in benign and malignant human bone tumors // Expert. Opin. Drug Metab. Toxicol. 2010. V. 4. P. 427 - 437.
Dohi O., Hatori M., Suzuki T. et al. Sex steroid receptors expression and hormone-induced cell proliferation in human osteosarcoma // Cancer Sci. 2008. V. 99. P. 518 - 523.
Degtyar' V.G., Babkina T.V., Kushlinskij N.E. i soavt. Obrazovanie 5α-digidrotetstosterona v opuxolyax kostej cheloveka razlichnogo gistologicheskogo stroeniya // Byull. e'ksp. biol. med. 1999. T. 26. № 7. S. 73 - 75.
Kushlinskij N.E., Bassaly'k L.S., Solov'ev Ju.N. i soavt. Polovy'e steroidny'e gormony' i osteogennaya sarkoma. Soobshhenie 1. Giperandrogeniya v patogeneze osteogennoj sarkomy' // Vestnik VONC RAMN. 1991. № 2. S. 7 - 12.
Wilson J.D. Role of androgens in male gender role behavior // Endocr. Rev. 1999. № 20. P. 726 - 737.
Degtyar' V.G., Kushlinskij N.E. Vosstanovlenie 5α-digidrotestosterona v kletkax-mishenyax polovy'x steroidov - katabolizm ili napravlennaya biotransformacziya v gormony' // Izvestiya RAN. Ser. biol. 1998. № 6. S. 664 - 669.
Degtyar' V.G., Kushlinskij N.E. 3α-Gidroksisteroid-degidrogenaza v tkanyax zhivotny'x i cheloveka // Bioximiya. 2001. № 66. S. 318 - 331.
Penning T.M. Molecular endocrinology of hydroxysteroid dehydrogenases // Endocr. Rev. 1997. № 18. P. 281 - 305.
Lutz L.B., Jamnongjit M., Yang W.H. Selective modulation of genomic and nongenomic androgen responses by androgen receptor ligands // Mol. Endocrinol. 2003. № 17. S. 1106 - 1116.
Chevalier S., Turcotte G., McKercher G. et al. Steroid metabolism and binding in relation to prostate cell growth and differentiation in vitro // Ann. N.Y. Acad. Sci. 1990. V. 595. P. 173 - 183.
Centrella M., McCarthy T.L., Chang W.Z. et al. Estren (4-estren-3alpha,17beta-diol) is a prohormone that regulates both androgenic and estrogenic transcriptional effects through the androgen receptor // Mol. Endocrinol. 2004. V. 18. P. 1120 - 1130.
Baniwal S.K., Khalid O., Sir D. et al. Repression of Runx2 by androgen receptor (AR) in osteoblasts and prostate cancer cells: AR binds Runx2 and abrogates its recruitment to DNA // Mol. Endocrinol. 2009. V. 23. P. 1203 - 1214.
Heinlein C.A., Chang C. The roles of androgen receptors and androgen-binding proteins in nongenomic androgen actions // Mol. Endocrinol. 2002. V. 16. P. 2181 - 2187.
Longhi A., Errani C., Gonzales-Arabio D. et al. Osteosarcoma in patients older than 65 years // J. Clin. Oncol. 2008. V. 26. P. 5368 - 5373.
Maki R.G. Pediatric sarcomas occurring in adults // J. Surg. Oncol. 2008. V. 97. P. 360 - 368.

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[2] Mejnuoring K. Mexanizmy' dejstviya androgenov. M.: Mir. 1976.

[3] Bruchovsky N., Wilson J.D. The conversion of testosterone to 5-alpha-androstan-17-beta-ol-3-one by rat prostate in vivo and in vitro // J. Biol. Chem. 1968. V. 243. P. 2012 - 2021.

[4] Bruchovsky N., Wilson J.D. The intranuclear binding of testosterone and 5-alpha-androstan-17-beta-ol-3-one by rat prostate // J. Biol. Chem. 1968. V. 243. P. 5953 - 5960.

[5] Chang Ch., Yeh Sh., Lee S.O., Chang Ta-min. Androgen Receptor (AR). Pathophysiological Roles in Androgen Related Diseases in Skin, Bone/Muscle, Metabolic Syndrome and Neuron/Immune Systems: Lessons Learned from Mice Lacking AR in Specific Cells // Nuclear Receptor Signaling. 2013. V. 11. P. e001.

[6] Gonzalez-Montelongo M.C., Marin R., Gomez T., Diaz M. Androgens are powerful non-genomic inducers of calcium sensitization in visceral smooth muscle // Steroids. 2010. V. 75. P. 533 - 538.

[7] Kushlinskij N.E., Degtyar' V.G. Metabolizm i mexanizm dejstviya androgenov. M.: RAMN. 2005.

[8] Degtyar' V.G., Kushlinskij N.E. Metabolizm androgenov // Uspexi sovremennoj biologii. 2000. T. 120. S. 48-59.

[9] Kang H.Y., Cho C.L., Huang K.L. et al. Nongenomic androgen activation of phosphatidylinositol 3-kinase/Akt signaling pathway in MC3T3-E1 osteoblasts // J. Bone Miner. Res. 2004. V.19. P. 1181 - 1190.

[10] Kang H.Y., Shyr C.R., Huang C.K. et al. Altered TNSALP expression and phosphate regulation contribute to reduced mineralization in mice lacking androgen receptor// Mol. Cell Biol. 2008. V. 28. P. 7354 - 7367.

[11] Pi M., Abby L. P., Darryl L.Q. GPRC6A Mediates the Non-genomic Effects of Steroids // J. Biol. Chem. 2010. V. 285. P. 39953 ? 39964.

[12] Albright F. The effect of hormones on osteogenesis in man // Recent. Prog. Horm. Res. 1947. V. 1. P. 293-353.

[13] Callewaert F., Boonen S., Vanderschueren D. Sex steroids and the male skeleton: a tale of two hormones // Trends Endocrinol. Metab. 2010. V. 21. P. 89-95.

[14] Foresta C., Ruzza G., Mioni R. Osteoporosis and decline of gonadal function in the elderly male // Hormone Res. 1984. V. 19. P. 18 - 22.

[15] Frenkel B., Hong A., Baniwal S.K. et al. Regulation of adult bone turnover by sex steroids // J. Cell Physiol. 2010. V. 224. P. 305-310.

[16] Gasperino J. Androgenic regulation of bone mass in women // Clin. Orthop. 1995. V. 311. P. 278 - 286.

[17] Vanderschueren D., Venken K., Ophoff J. et al. Clinical Review: Sex steroids and the periosteum-reconsidering the roles of androgens and estrogens in periosteal expansion // J. Clin. Endocrinol. Metab. 2006. V. 91. P. 378 - 382.

[18] Vandenput L., Ohlsson C. Sex steroid metabolism in the regulation of bone health in men // J. Steroid Biochem. Mol. Biol. 2010. V. 121. P. 582 - 588.

[19] Tsai M.Y., Shyr C.R., Kang H.Y. et al. The reduced trabecular bone mass of adult ARKO male mice results from the decreased osteogenic differentiation of bone marrow stroma cells // Biochem. Biophys. Res. Commun. 2011. V. 411. P. 477-482.

[20] Carnevale V., Romagnoli E., Cipriani C. et al. Sex hormones and bone in health males // Arch. Biochem. Biophys. 2010. V. 503. P. 110 - 117.

[21] Sinnesael M., Claessens F., Lauren M. et al. Androgen receptor (AR) in osteocytes is important for the maintenance of male skeletal integrity: evidence from targeted AR disruption in mouse osteocytes // J. Bone Miner. Res. 2012. V. 27. P. 2535 - 2543.

[22] McEwan I.J. Androgen receptor modulators: a marriage of chemistry and biology // Future Med. Chem. 2013. V. 5. P. 1109-1120.

[23] Chiang C., Chiu M., Moore A.J. et al. Mineralization and bone resorption are regulated by the androgen receptor in male mice // J. Bone Miner. Res. 2009. V. 24. P. 621 - 631.

[24] Notini A.J., McManus J.F., Moore A. et al. Osteoblast deletion of exon 3 of the androgen receptor gene results in trabecular bone loss in adult male mice // J. Bone Miner. Res. 2007. V. 22. P. 347 ? 356.

[25] Almeida M., Han L., Martin-Millan M. et al. Skeletal involution by age-associated oxidative stress and its acceleration by loss of sex steroids // J. Biol. Chem. 2007. V. 282. P. 27285 - 27297.

[26] Czerwiec F.S., Liaw J.J., Liu S.B. et al. Absence of androgen transcriptional effects in osteoblastic cells despite presence of androgen receptors // Bone. 1997. V. 21. P. 49 - 56.

[27] Kushlinskij N.E., Bassaly'k L.S., Solov'ev Ju.N. i dr. Polovy'e steroidny'e gormony' i osteogennaya sarkoma. Soobshhenie 1. Giperandrogeniya v patogeneze osteogennoj sarkomy' // Vestnik VONC RAMN. 1991. V. 2. P. 7 - 12.

[28] Sergeev P.V., Chukaev S.A., Gorbatenko E.V., Kushlinskij N.E. Soderzhanie testosterona i aktivnost' fermenta 5α-steroid-NAD(P)Δ4-oksidoreduktazy' v normal'noj kostnoj tkani i zlokachestvenny'x opuxolyax kostej // Byull. e'ksp. biol. med. 1997. T. 24. № 9. S. 305 - 307.

[29] Nakano Y., Morimoto I., Ishida O. et al. The receptor, metabolism and effects of androgen in osteoblastic MC3T3-E1 cells // Bone Mineral. 1994. V. 26. P. 245 - 259.

[30] Ribot C., Fromolliers F. Sex steroids and bone tissue // Ann. Endocrinol. 1995. V. 56. P. 49-55.

[31] Svoboda M., Hamilton G., Thalhammer T. Steroid hormone metabolizing enzymes in benign and malignant human bone tumors // Expert. Opin. Drug Metab. Toxicol. 2010. V. 4. P. 427 - 437.

[32] Dohi O., Hatori M., Suzuki T. et al. Sex steroid receptors expression and hormone-induced cell proliferation in human osteosarcoma // Cancer Sci. 2008. V. 99. P. 518 - 523.

[33] Degtyar' V.G., Babkina T.V., Kushlinskij N.E. i soavt. Obrazovanie 5α-digidrotetstosterona v opuxolyax kostej cheloveka razlichnogo gistologicheskogo stroeniya // Byull. e'ksp. biol. med. 1999. T. 26. № 7. S. 73 - 75.

[34] Kushlinskij N.E., Bassaly'k L.S., Solov'ev Ju.N. i soavt. Polovy'e steroidny'e gormony' i osteogennaya sarkoma. Soobshhenie 1. Giperandrogeniya v patogeneze osteogennoj sarkomy' // Vestnik VONC RAMN. 1991. № 2. S. 7 - 12.

[35] Wilson J.D. Role of androgens in male gender role behavior // Endocr. Rev. 1999. № 20. P. 726 - 737.

[36] Degtyar' V.G., Kushlinskij N.E. Vosstanovlenie 5α-digidrotestosterona v kletkax-mishenyax polovy'x steroidov - katabolizm ili napravlennaya biotransformacziya v gormony' // Izvestiya RAN. Ser. biol. 1998. № 6. S. 664 - 669.

[37] Degtyar' V.G., Kushlinskij N.E. 3α-Gidroksisteroid-degidrogenaza v tkanyax zhivotny'x i cheloveka // Bioximiya. 2001. № 66. S. 318 - 331.

[38] Penning T.M. Molecular endocrinology of hydroxysteroid dehydrogenases // Endocr. Rev. 1997. № 18. P. 281 - 305.

[39] Lutz L.B., Jamnongjit M., Yang W.H. Selective modulation of genomic and nongenomic androgen responses by androgen receptor ligands // Mol. Endocrinol. 2003. № 17. S. 1106 - 1116.

[40] Chevalier S., Turcotte G., McKercher G. et al. Steroid metabolism and binding in relation to prostate cell growth and differentiation in vitro // Ann. N.Y. Acad. Sci. 1990. V. 595. P. 173 - 183.

[41] Centrella M., McCarthy T.L., Chang W.Z. et al. Estren (4-estren-3alpha,17beta-diol) is a prohormone that regulates both androgenic and estrogenic transcriptional effects through the androgen receptor // Mol. Endocrinol. 2004. V. 18. P. 1120 - 1130.

[42] Baniwal S.K., Khalid O., Sir D. et al. Repression of Runx2 by androgen receptor (AR) in osteoblasts and prostate cancer cells: AR binds Runx2 and abrogates its recruitment to DNA // Mol. Endocrinol. 2009. V. 23. P. 1203 - 1214.

[43] Heinlein C.A., Chang C. The roles of androgen receptors and androgen-binding proteins in nongenomic androgen actions // Mol. Endocrinol. 2002. V. 16. P. 2181 - 2187.

[44] Longhi A., Errani C., Gonzales-Arabio D. et al. Osteosarcoma in patients older than 65 years // J. Clin. Oncol. 2008. V. 26. P. 5368 - 5373.

[45] Maki R.G. Pediatric sarcomas occurring in adults // J. Surg. Oncol. 2008. V. 97. P. 360 - 368.

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