Summary
The polypeptide growth factors insulin-like growth factor I (IGF-I), epidermal growth factor (EGF), and transforming growth factor-α (TGF-α); second-messenger cyclic adenosine monophosphate (cAMP); protein kinase activators; and neurotransmitters were found to activate the estrogen (ER), progesterone (PR), and glucocorticoid receptor (GR) either in the absence of their natural ligands or synergistically with the respective hormone. There is now evidence of coupling of signaling pathways involving the androgen receptor (AR). Three polypeptide growth factors, IGF-I, keratinocyte growth factor (KGF), and EGF, stimulated AR-mediated reporter-gene transcription in the absence of androgen in DU-145 cells, which were cotransfected with the reporter gene and an AR expression vector. IGF-I effects were observed irrespective of the promoter driving the reporter gene. This growth factor increased the prostate-specific antigen (PSA) level in LNCaP cells, which contain endogenous AR. In CV-1 cells, which transiently express the AR, second-messenger cAMP potentiated effects of testosterone in stimulation of AR-mediated reporter-gene activity. Inhibition of androgen-stimulated chloramphenicol acetyltransferase (CAT) activity in the LNCaP cell line was achieved with retinoic acid. Stimulation and inhibition of prostatic carcinoma cell growth by polypeptide growth factors and cellular regulators may depend on the presence of the AR in an androgen-depleted environment.
Article PDF
Similar content being viewed by others
Avoid common mistakes on your manuscript.
References
Andrews PE, Young CYF, Montgomery BT, Tindall DJ (1992) Tumor-promoting phorbol ester down-regulates the androgen induction of prostate-specific antigen in a human prostatic adenocarcinoma cell line. Cancer Res 52:1525–1529
Aronica SM, Katzenellenbogen BS (1991) Progesterone receptor regulation in uterine cells: stimulation by estrogen, cyclic adenosine 3'5'-monophosphate, and insulin-like growth factor I and suppression by antiestrogens and protein kinase inhibitors. Endocrinology 128:2045–2052
Aronica SM, Katzenellenbogen BS (1993) Stimulation of estrogen receptor-mediated transcription and alteration in the phosphorylation state of the rat uterine estrogen receptor by estrogen, cyclic adenosine monophosphate, and insulin-like growth factor-I. Mol Endocrinol 7:743–752
Centrelia M, McCarthy TL, Canalis E (1990) Receptors for insulin-like growth factors-I and -II in osteoblast-enriched cultures from fetal rat bone. Endocrinology 126:39–44
Cho H, Katzenellenbogen BS (1993) Synergistic activation of estrogen receptor-mediated transcription by estradiol and protein kinase activators. Mol Endocrinol 7:441–452
Cohen P, Peehl DM, Lamson G, Rosenfeld RG (1991) Insulinlike growth factors (IGFs), IGF receptors, and IGF-binding proteins in primary cultures of prostate epithelial cells. J Clin Endocrinol Metab 73:401–407
Cohen P, Graves HCB, Peehl DM, Kamarei M, Guidice LC, Rosenfeld RG (1992) Prostate-specific antigen (PSA) is an insulin-like growth factor binding protein-3 protease found in seminal plasma. J Clin Endocrinol Metab 75:1046–1053
Cohen P, Peehl DM, Stamey TA, Wilson KF, Clemmons DR, Rosenfeld RG (1993) Elevated levels of insulin-like growth factor-binding protein-2 in the serum of prostate cancer patients. J Clin Endocrinol Metab 76:1031–1035
Connolly JM, Rose DP (1994) Regulation of DU-145 human prostate cancer cell proliferation by insulin-like growth factors and its interaction with the epidermal growth factor autocrine loop. Prostate 24:167–175
Culig Z, Hobisch A, Cronauer MV, Cato ACB, Hittmair A, Radmayr C, Eberle J, Bartsch G, Klocker H (1993) Mutant androgen receptor detected in an advanced stage of prostatic carcinoma is activated by adrenal androgens and progesterone. Mol Endocrinol 7:1541–1550
Culig Z, Hobisch A, Cronauer MV, Radmayr C, Trapman J, Hittmair A, Bartsch G, Klocker H (1994) Androgen receptor activation in prostatic tumor cell lines by insulin-like growth factor-I, keratinocyte growth factor and epidermal growth factor. Cancer Res 54:5474–5478
Dickson RB, Manaway ME, Lippman ME (1986) Estrogen-induced factors of breast cancer cells partially replace estrogen to promote tumor growth. Science 232:1540–1543
Hembree JR, Agarwal C, Eckert RL (1994) Epidermal growth factor suppresses insulin-like growth factor binding protein 3 levels in human papillomavirus type 16-immortalized cervical epithelial cells and thereby potentiates the effects of insulin-like growth factor-I. Cancer Res 54:3160–3166
Ignar-Trowbridge DM, Nelson KG, Bidwell MC, Curtis SW, Washburn TF, McLachlan JA, Korach KS (1992) Coupling of dual signaling pathways: epidermal growth factor action involves the estrogen receptor. Proc Natl Acad Sci USA 89:4658–4662
Ignar-Trowbridge DM, Teng CT, Ross KA, Parker MG, Korach KS, McLachlan JA (1993) Peptide growth factors elicit estrogen receptor-dependent transcriptional activation of an estrogen-responsive element. Mol Endocrinol 7:992–998
Ikonen T, Palvimo JJ, Kallio PJ, Reinikainen P, Jänne OA (1994) Stimulation of androgen-regulated transactivation by modulators of protein phosphorylation. Endocrinology 135:1359–1366
Iwamura M, Sluss PM, Casamento JB, Cockett ATK (1993) Insulin-like growth factor-I: action and receptor characterization in human prostate cancer cell lines. Prostate 22:243–252
Kaneti H, Madjar Y, Dagan Y, Levi J, Papa MZ, Pariente C, Goldwasser B, Karasik A (1993) Serum insulin-like growth factor-binding protein-2 (IGFBP-2) is increased and IGFBP-3 is decreased in patients with prostate cancer: correlation with serum prostate-specific antigen. J Clin Endocrinol Metab 77:229–233
Katzenellenbogen BS, Norman MJ (1990) Multihormonal regulation of the progesterone receptor in MCF-7 human breast cancer cells: interrelationships among insulin/insulin-like growth factor-I, serum, and estrogen. Endocrinology 126:891–898
Kokontis J, Takakura K, Hay N, Liao S (1994) Increased androgen receptor activity and altered c-myc expression in prostate cancer cells after long-term androgen deprivation. Cancer Res 54:1566–1573
Krongrad A, Bai G (1994) c-fos Insensitivity to phorbol ester and possible role of protein kinase C in androgen-independent cancer cells. Cancer Res 54:6073–6077
Krusekopf S, Chaucherau A, Milgrom E, Henderson D, Cato ACB (1991) Cooperation of progestational steroids with epidermal growth factor in activation of gene expression in mammary tumor cells. J Steroid Biochem Mol Biol 40:239–245
Kwast TH van der, Schalken J, Ruizeveld de Winter JA, Vroonhoven CCJ van, Mulder E, Boersma W, Trapman J (1991) Androgen receptors in endocrine therapy resistant prostate cancer. Int J Cancer 48:189–193
Ma ZQ, Santagati S, Patrone C, Pollio G, Vegeto E, Maggi A (1994) Insulin-like growth factors activate estrogen receptor to control the growth and differentiation of the human neuroblastoma cell line SK-ER3. Mol Endocrinol 8:910–918
Montgomery BT, Young CYF, Bilhartz DL, Andrews PE, Prescott JL, Thompson NF, Tindall DJ (1992) Hormonal regulation of prostate-specific antigen (PSA) glycoprotein in the human prostatic adenocarcinoma cell line, LNCaP. Prostate 21:63–73
Murphy LJ, Murphy LC, Friesen HG (1987) Estrogen induces insulin-like growth factor-I expression in the rat uterus. Mol Endocrinol 1:445–450
Nelson KG, Takanashi TT, Bossert NL, Walmer DK, McLachlan JA (1991) Epidermal growth factor replaces estrogen in the stimulation of female genital-tract growth and differentiation. Proc Natl Acad Sci USA 88:21–25
Newmark JR, Hardy DO, Tonb DC, Carter BS, Epstein JI, Isaacs WB, Brown TR, Barrack ER (1992) Androgen receptor gene mutations in human prostate cancer. Proc Natl Acad Sci USA 89:6319–6323
Newton CJ, Buric R, Trapp T, Brockmeier S, Pagotto U, Stalla GK (1994) The unliganded estrogen receptor (ER) transduces growth factor signals. J Steroid Biochem Mol Biol 48:481–486
Nordeen SK, Moyer ML, Bona BJ (1994) The coupling of multiple signal transduction pathways with steroid response mechanisms. Endocrinology 134:1723–1732
Pietrzkowski Z, Mulholland G, Gomella L, Jameson BA, Wernicke D, Baserga R (1993) Inhibition of prostatic cancer cell lines by peptide analogues of insulin-like growth factor-I. Cancer Res 53:1102–1106
Power RF, Lyndon JP, Connely OM, O'Malley BW (1992) Dopaminergic and ligand-independent activation of steroid hormone receptors. Science 254:1636–1639
Reiter E, Bonnet P, Sente B, Dombrowicz D, Leval J de, Closset J, Hennen G (1992) Growth hormone and prolactin stimulate androgen receptor, insulin-like growth factor-I (IGF-I) and IGF-I receptor levels in the prostate of immature rats. Mol Cell Endocrinol 88:77–87
Reiter E, Lardinois S, Klug M, Bruyninx M, Hennuy B, Closset J, Hennen G (1994) Androgen-independent effects of growth hormone and prolactin on the different lobes of the rat prostate. Proceedings, American Association for Cancer Research special conference on the basic and clinical aspects of prostate cancer, Palm Springs, December 8–12, 1994
Riegman PHJ, Vlietstra RJ, Korput JAGM van der, Brinkmann AO, Trapman J (1991) The promoter of the prostate-specific antigen contains a functional androgen responsive element. Mol Endocrinol 5:1921–1930
Sadi MV, Walsh PC, Barrack ER (1993) Immunohistochemical study of androgen receptors in metastatic prostate cancer — comparison of receptor content and response to hormonal therapy. Cancer 67:3057–3064
Sartorius CA, Groshong SD, Miller LA, Powell RL, Tung L, Takimoto GS, Horwitz KB (1994) New T47D breast cancer cells for the independent study of progesterone B- and A-receptors: only antiprogestin occupied B-receptors are switched to transcriptional agonists by cAMP. Cancer Res 54:3868–3877
Suzuki H, Sato N, Watabe Y, Masai M, Seino, Shimazaki J (1993) Androgen receptor gene mutations in human prostate cancer. J Steroid Biochem Mol Biol 46:759–765
Taplin ME, Bubley G, Frantz M, Balk SP (1994) Androgen receptor mutations in human hormone-independent prostate cancer. Proc Am Assoc Cancer Res 35:1630
Turgeon JL, Waring DW (1994) Activation of the progesterone receptor by the gonadotropin-releasing hormone self-priming signaling pathway. Mol Endocrinol 8:860–869
Veldscholte J, Ris-Stalpers C, Kuiper GGJM, Jenster G, Berrevoets C, Claassen E, Rooji HCJ van, Trapman J, Brinkmann AO, Mulder E (1990) A mutation in the ligand binding domain of the androgen receptor of human LNCaP cells affects steroid binding characteristics and response to anti-androgens. Biochem Biophys Res Commun 17:534–540
Yan G, Fukabori Y, Nikolaropoulos S, Wang F, McKeehan WL (1992) Heparin-binding keratinocyte growth factor is a candidate stromal to epithelial cell andromedin. Mol Endocrinol 6:2123–2128
Young CYF, Murtha PE, Andrews PE, Lindzey JK, Tindall DJ (1994) Antagonism of androgen action in prostate tumor cells by retinoic acid. Prostate 25:39–45
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Culig, Z., Hobisch, A., Cronauer, M.V. et al. Activation of the androgen receptor by polypeptide growth factors and cellular regulators. World J Urol 13, 285–289 (1995). https://doi.org/10.1007/BF00185971
Issue Date:
DOI: https://doi.org/10.1007/BF00185971