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系統識別號 U0026-0812200914183877
論文名稱(中文) 蟲草素活化小鼠萊氏細胞固醇類生合成之訊息傳遞研究
論文名稱(英文) Study of Signal Transduction Pathways Activated by Cordycepin on Steroidogenesis in Mouse Leydig Cells
校院名稱 成功大學
系所名稱(中) 細胞生物及解剖學研究所
系所名稱(英) Institute of Cell Biology and Anatomy
學年度 96
學期 2
出版年 97
研究生(中文) 包翔引
研究生(英文) Hsiang-Yin Pao
電子信箱 t9695105@mail.ncku.edu.tw
學號 t9695105
學位類別 碩士
語文別 英文
論文頁數 73頁
口試委員 口試委員-莫凡毅
口試委員-蔡少正
口試委員-郭余民
口試委員-黃步敏
指導教授-黃步敏
中文關鍵字 MTT細胞活性檢測  睪固酮  腹腔內注射  C57BL/6 (B6)小鼠  增生因子活化激酶  磷脂酶C  蛋白激酶C  固醇類生合成速控蛋白  固醇類生合成  蟲草素  MA-10 
英文關鍵字 Cordycepin  mitogen-induced protein kinase (MAPK)  C57BL/6 (B6) mice  MA-10 mouse Leydig tumor cell  calcium-dependent protein kinase C (PKC)  testosterone  phospholipase C (PLC)  steroidogenic acute regulatory (StAR) protein  intraperitoneal (IP) injection  MTT cell viability assay  steroidogenesis 
學科別分類
中文摘要 蟲草素 (3’-去氧腺苷酸) 是一種純化自冬蟲夏草的腺苷酸類似物,在中國傳統醫學上廣泛的被用來降低疲勞、調節肺部及慢性炎症,甚至是癌症等疾病。根據我們之前的研究指出,蟲草素可能會藉由腺苷酸受器 (A1, A2a和A3亞型) 而活化細胞中固醇類速控蛋白表現,進而調節正常小鼠萊氏細胞固醇類生合成。相同的,此一刺激性的反應也能夠在MA-10小鼠萊氏腫瘤細胞上被觀察到。然而,蟲草素究竟是透過何種細胞內訊息傳遞路徑去影響MA-10細胞則還未知。在這裡,我們假設蟲草素可能經由活化腺苷酸受器去調控細胞內環單磷酸腺苷/蛋白激酶A路徑,進而增進萊氏細胞固醇類生合成。為了驗證蟲草素可以調節萊氏細胞固醇類生合成,在此實驗中我們利用放射免疫分析法和免疫墨點法去偵測固醇類荷爾蒙產量和特定蛋白質的表現量。結果顯示,十二或二十四小時蟲草素 (100 μM) 的刺激下,能夠顯著地使MA-10細胞產生黃體激素 (p < 0.01) 達三倍之多。GF109203X (蛋白激酶C抑制劑;1 μM)、U73122 (磷脂酶C抑制劑;20 μM) 和sodium orthovanadate (肌醇三磷酸活化鈣離子通道抑制劑;40 μM) 能夠顯著地抑制蟲草素所引發的黃體激素產量 (p < 0.05)。反之,H89 (蛋白激酶A抑制劑;5 ~ 100 μM)、wortmannin (磷酸肌醇3激酶抑制劑;10 ~ 200 nM)、U0126 (增生因子活化激酶/細胞外訊息調節激酶1/2抑制劑;1 ~ 20 μM)、PD98059 (細胞外訊息調節激酶1/2抑制劑;5 ~ 50 μM )、SB202190 (p38增生因子活化激酶抑制劑;1 ~ 25 μM) 和SP600125 (c-Jun N端蛋白質激酶抑制劑;20 ~ 500 nM) 則沒有此種抑制性的效果。有趣的是,U0126 (20 μM) 和SP600125 (500 nM) 作用下會進一步增加蟲草素所引發的黃體激素產量分別達 2.5 和1.8 倍之多 (p < 0.05)。蟲草素處理之下MA-10細胞中固醇類生合成速控蛋白的表現量並沒有增加的趨勢,但是增加的現象卻可以顯著地在PD98059 (細胞外訊息調節激酶1/2抑制劑;50 μM) 和U0126 (增生因子活化激酶/細胞外訊息調節激酶1/2抑制劑;20 μM) 單獨處理或是和蟲草素共處理後被觀察到 (p < 0.05)。細胞外訊息調節激酶1/2和c-Jun N端蛋白質激酶磷酸化蛋白表現量的增加現象可以在十五分鐘後被偵測出來 (p < 0.05)。更進一步的,我們發現抑制細胞中蛋白激酶C會顯著地增強蟲草素活化的細胞外訊息調節激酶1/2磷酸化蛋白的表現,似乎告訴我們細胞外訊息調節激酶1/2在蟲草素引發的固醇類生合成中可能扮演著抑制性的角色。再者,我們將蟲草素 (40 mg/kg) 連續七天經由腹腔注射到六週大的B6小鼠體內,七天後將老鼠犧牲並測量其血液中睪固酮含量及生殖器官重量。結果顯現,七天的蟲草素處理能夠顯著的增加小鼠睪丸重量和血液中睪固酮含量 (p < 0.05)。此外,利用細胞型態觀察和MTT細胞活性檢測,我們也證實了,蟲草素造成MA-10細胞死亡可能是經由蛋白激酶C路徑的活化而引發。此一細胞死亡現象不是由蟲草素刺激MA-10細胞所造成的黃體激素累積而產生。總括來說,我們發現,蟲草素可以顯著的在in vitro及in vivo實驗中引發小鼠萊氏細胞固醇類生合成,此刺激現象可能透過蛋白激酶C和增生因子活化型蛋白激酶訊息傳遞路徑。此外,蟲草素也可能透過蛋白激酶C訊息傳遞路徑引發MA-10小鼠萊氏腫瘤細胞死亡。
英文摘要 Cordycepin (3'-deoxyadenosine) is an adenosine analog isolated from Cordyceps sinensis, which is a widespread component used in traditional Chinese medicine to reduce fatigue, and is prescribed for various diseases, such as pulmonary disease, chronic inflammation or even cancer therapy. Previously, we have demonstrated that cordycepin might act through the adenosine receptors (A1, A2a, and A3 subtypes) to activate StAR protein expression and regulate steroidogenesis in normal mouse Leydig cells. Correspondingly, the stimulatory effect could also be observed in MA-10 mouse Leydig tumor cells. However, the intracellular signal transduction pathways mediated by cordycepin in MA-10 cells remain unclear. Here, we hypothesized that cordycepin may act through adenosine receptors to induce cAMP/PKA signal transduction pathway and regulate steroidogenesis in Leydig cells. To investigate whether cordycepin can regulate Leydig cell steroidogenesis, radioimmunoassay and immunoblot assay were used in this study to determine steroidogenic hormones production and specific protein expression. Results demonstrated that, compared to control, 100 μM cordycepin significantly induced progesterone production in MA-10 cells (p < 0.01). This stimulatory effect reached 3-fold after 12 and 24 hr treatment. GF109203X (PKC inhibitor; 1 μM), U73122 (PLC inhibitor; 20 μM), and sodium orthovanadate (IP3-Ca2+ inhibitor; 40 μM) significantly inhibited cordycepin-activated progesterone production (p < 0.05), whereas H89 (PKA inhibitor; 5 ~ 100 μM), wortmannin (PI3K inhibitor; 10 ~ 200 nM), U0126 (MEK1/2 inhibitor; 1 ~ 20 μM), PD98059 (ERK1/2 inhibitor; 5 ~ 50 μM ), SB202190 (p38 MAPK inhibitor; 1 ~ 25 μM), and SP600125 (JNK inhibitor; 20 ~ 500 nM) did not. Interestingly, U0126 (1 μM) and SP600125 (500 nM) enhance cordycepin-mediated progesterone production for 2.5 and 1.8 folds (p < 0.05), respectively. The increasing trend of steroidogenic acute regulatory (StAR) protein expression in MA-10 cells was not observed under cordycepin treatment, but the increasing effect could be significantly observed after PD98059 (ERK1/2 inhibitor; 50 μM) and U0126 (MEK1/2 inhibitor; 20 μM) alone treatment or co-treatment of cordycepin compared to control (p < 0.05). In contrast, the phosphorylation of ERK 1/2 and JNK could be detected after 15 min cordycepin treatment (p < 0.05). Moreover, the inhibition of PKC significantly enhance the expression of cordycepin-activated ERK1/2 protein phosphorylation (p < 0.05), suggesting that ERK1/2 might have inhibitory role on cordycepin-activated steroidogenesis. Furthermore, the cordycepin (40 mg/kg) was administrated by intraperitoneal (IP) injection into 6-week old male B6 mouse to investigate its effect in vivo. Data illustrated that 7-day cordycepin treatment would increase the testes weight and plasma testosterone concentration (p < 0.05). In addition, with cell morphological observation and MTT cell viability assay, we also demonstrated that cordycepin caused MA-10 cell death, which was possible through the activation of PKC pathway. This death effect was not caused by the accumulation of progesterone, which was produced by MA-10 cell induced by cordycepin. Together, our study demonstrated that cordycepin significantly induced mouse Leydig cell steroidogenesis both in vitro and in vivo, and this effect might go through PKC and MAPK signal transduction pathways. Moreover, cordycepin might activate PKC signal transduction pathway to induce MA-10 mouse Leydig tumor cell death.
論文目次 中文摘要---I
ABSTRACT---IV
誌謝---VII
TABLE OF CONTENTS---IX
LIST OF TABLES---XI
LIST OF FIGURES---XII
INTRODUCTION---1
MATERIALS AND METHODS---7
CHEMICALS---7
ANIMALS---8
MICE INTRAPERITONEAL INJECTION---9
COLLECTION OF BLOOD SAMPLES---9
PLASMA TESTOSTERONE EXTRACTION AND MEASUREMENT---10
MEASUREMENT OF REPRODUCTIVE ORGANS WEIGHS---10
ISOLATION OF LEYDIG CELLS---11
MA-10 CELL CULTURE---12
RADIOIMMUNOASSAY (RIA)---12
MTT CELL VIABILITY ASSAY---14
IMMUNOBLOT ANALYSIS---14
STATISTICS---16
RESULTS---18
THE IN VIVO EFFECT OF CORDYCEPIN ON BODY WEIGHT, REPRODUCTIVE ORGAN WEIGHTS, AND PLASMA TESTOSTERONE CONCENTRATION IN MICE---18
THE TIME AND DOSE EFFECTS OF CORDYCEPIN ON PROGESTERONE PRODUCTION IN MA-10 CELLS---19
THE EFFECTS OF PKA, PI3K, PKC, PLC, AND IP3-CA2+ PROTEIN KINASE INHIBITORS ON CORDYCEPIN-ACTIVATED PROGESTERONE PRODUCTION IN MA-10 CELLS---19
THE EFFECTS OF MAPK PROTEIN KINASE INHIBITORS ON CORDYCEPIN-ACTIVATED PROGESTERONE PRODUCTION IN MA-10 CELLS---20
THE EFFECT OF CORDYCEPIN ON STAR PROTEIN EXPRESSIONS IN MA-10 CELLS---21
THE EFFECT OF CORDYCEPIN ON P38, JNK, ERK1/2 PROTEIN EXPRESSIONS IN MA-10 CELLS---22
THE EFFECT OF CORDYCEPIN ON CELL MORPHOLOGY AND CELL VIABILITY IN MA-10 CELLS---23
THE EFFECT OF CORDYCEPIN AND CO-TREATMENT OF DIFFERENT PROTEIN KINASE INHIBITORS ON MORPHOLOGICAL AND CELL VIABILITY CHANGES IN MA-10 CELLS---23
THE EFFECT OF CORDYCEPIN AND PROGESTERONE ON MORPHOLOGY AND CELL VIABILITY IN MA-10 CELLS---24
DISCUSSION---26
REFERENCES---59
ABOUT THE AUTHOR---73
參考文獻 1. Leung, P.C. and G.L. Steele, Intracellular signaling in the gonads. Endocr Rev, 1992. 13(3): p. 476-98.
2. Miller, W.L., Molecular biology of steroid hormone synthesis. Endocr Rev, 1988. 9(3): p. 295-318.
3. Payne, A.H. and G.L. Youngblood, Regulation of expression of steroidogenic enzymes in Leydig cells. Biol Reprod, 1995. 52(2): p. 217-25.
4. Hanukoglu, I. and R. Rapoport, Routes and regulation of NADPH production in steroidogenic mitochondria. Endocr Res, 1995. 21(1-2): p. 231-41.
5. Stocco, D.M. and B.J. Clark, Regulation of the acute production of steroids in steroidogenic cells. Endocr Rev, 1996. 17(3): p. 221-44.
6. Sugawara, T., D. Lin, J.A. Holt, K.O. Martin, N.B. Javitt, W.L. Miller, and J.F. Strauss, 3rd, Structure of the human steroidogenic acute regulatory protein (StAR) gene: StAR stimulates mitochondrial cholesterol 27-hydroxylase activity. Biochemistry, 1995. 34(39): p. 12506-12.
7. Priyanka, S. and R. Medhamurthy, Characterization of cAMP/PKA/CREB signaling cascade in the bonnet monkey corpus luteum: expressions of inhibin-alpha and StAR during different functional status. Mol Hum Reprod, 2007. 13(6): p. 381-90.
8. Saez, J.M., Leydig cells: endocrine, paracrine, and autocrine regulation. Endocr Rev, 1994. 15(5): p. 574-626.
9. Marinissen, M.J. and J.S. Gutkind, G-protein-coupled receptors and signaling networks: emerging paradigms. Trends Pharmacol Sci, 2001. 22(7): p. 368-76.
10. Cameron, M.R., J.S. Foster, A. Bukovsky, and J. Wimalasena, Activation of mitogen-activated protein kinases by gonadotropins and cyclic adenosine 5'-monophosphates in porcine granulosa cells. Biol Reprod, 1996. 55(1): p. 111-9.
11. Renlund, N., Y. Jo, I. Svechnikova, M. Holst, D.M. Stocco, O. Soder, and K. Svechnikov, Induction of steroidogenesis in immature rat Leydig cells by interleukin-1alpha is dependent on extracellular signal-regulated kinases. J Mol Endocrinol, 2006. 36(2): p. 327-36.
12. Robinson, M.J. and M.H. Cobb, Mitogen-activated protein kinase pathways. Curr Opin Cell Biol, 1997. 9(2): p. 180-6.
13. Hibi, M., A. Lin, T. Smeal, A. Minden, and M. Karin, Identification of an oncoprotein- and UV-responsive protein kinase that binds and potentiates the c-Jun activation domain. Genes Dev, 1993. 7(11): p. 2135-48.
14. Seger, R. and E.G. Krebs, The MAPK signaling cascade. FASEB J, 1995. 9(9): p. 726-35.
15. Seger, R., T. Hanoch, R. Rosenberg, A. Dantes, W.E. Merz, J.F. Strauss, 3rd, and A. Amsterdam, The ERK signaling cascade inhibits gonadotropin-stimulated steroidogenesis. J Biol Chem, 2001. 276(17): p. 13957-64.
16. Hiipakka, R.A. and S. Liao, Molecular mechanism of androgen action. Trends Endocrinol Metab, 1998. 9(8): p. 317-24.
17. Mahmoud, A. and F.H. Comhaire, Mechanisms of disease: late-onset hypogonadism. Nat Clin Pract Urol, 2006. 3(8): p. 430-8.
18. Sun, Y.T., D.C. Irby, D.M. Robertson, and D.M. de Kretser, The effects of exogenously administered testosterone on spermatogenesis in intact and hypophysectomized rats. Endocrinology, 1989. 125(2): p. 1000-10.
19. Traish, A.M., I. Goldstein, and N.N. Kim, Testosterone and erectile function: from basic research to a new clinical paradigm for managing men with androgen insufficiency and erectile dysfunction. Eur Urol, 2007. 52(1): p. 54-70.
20. Zitzmann, M. and E. Nieschlag, Testosterone levels in healthy men and the relation to behavioural and physical characteristics: facts and constructs. Eur J Endocrinol, 2001. 144(3): p. 183-97.
21. Li, S.P., F.Q. Yang, and K.W. Tsim, Quality control of Cordyceps sinensis, a valued traditional Chinese medicine. J Pharm Biomed Anal, 2006. 41(5): p. 1571-84.
22. Zhu, J.S., G.M. Halpern, and K. Jones, The scientific rediscovery of an ancient Chinese herbal medicine: Cordyceps sinensis: part I. J Altern Complement Med, 1998. 4(3): p. 289-303.
23. Zhu, J.S., G.M. Halpern, and K. Jones, The scientific rediscovery of a precious ancient Chinese herbal regimen: Cordyceps sinensis: part II. J Altern Complement Med, 1998. 4(4): p. 429-57.
24. Yamaguchi, Y., S. Kagota, K. Nakamura, K. Shinozuka, and M. Kunitomo, Antioxidant activity of the extracts from fruiting bodies of cultured Cordyceps sinensis. Phytother Res, 2000. 14(8): p. 647-9.
25. Li, S.P., K.J. Zhao, Z.N. Ji, Z.H. Song, T.T. Dong, C.K. Lo, J.K. Cheung, S.Q. Zhu, and K.W. Tsim, A polysaccharide isolated from Cordyceps sinensis, a traditional Chinese medicine, protects PC12 cells against hydrogen peroxide-induced injury. Life Sci, 2003. 73(19): p. 2503-13.
26. Liu, C., S. Lu, and M.R. Ji, [Effects of Cordyceps sinensis (CS) on in vitro natural killer cells]. Zhongguo Zhong Xi Yi Jie He Za Zhi, 1992. 12(5): p. 267-9, 59.
27. Xu, R.H., X.E. Peng, G.Z. Chen, and G.L. Chen, Effects of Cordyceps sinensis on natural killer activity and colony formation of B16 melanoma. Chin Med J (Engl), 1992. 105(2): p. 97-101.
28. Chen, Y.J., M.S. Shiao, S.S. Lee, and S.Y. Wang, Effect of Cordyceps sinensis on the proliferation and differentiation of human leukemic U937 cells. Life Sci, 1997. 60(25): p. 2349-59.
29. Yoshida, J., S. Takamura, N. Yamaguchi, L.J. Ren, H. Chen, S. Koshimura, and S. Suzuki, Antitumor activity of an extract of Cordyceps sinensis (Berk.) Sacc. against murine tumor cell lines. Jpn J Exp Med, 1989. 59(4): p. 157-61.
30. Hsu, C.C., S.J. Tsai, Y.L. Huang, and B.M. Huang, Regulatory mechanism of Cordyceps sinensis mycelium on mouse Leydig cell steroidogenesis. FEBS Lett, 2003. 543(1-3): p. 140-3.
31. Hsu, C.C., Y.L. Huang, S.J. Tsai, C.C. Sheu, and B.M. Huang, In vivo and in vitro stimulatory effects of Cordyceps sinensis on testosterone production in mouse Leydig cells. Life Sci, 2003. 73(16): p. 2127-36.
32. Huang, Y.L., S.F. Leu, B.C. Liu, C.C. Sheu, and B.M. Huang, In vivo stimulatory effect of Cordyceps sinensis mycelium and its fractions on reproductive functions in male mouse. Life Sci, 2004. 75(9): p. 1051-62.
33. Chen, Y.C., Y.L. Huang, and B.M. Huang, Cordyceps sinensis mycelium activates PKA and PKC signal pathways to stimulate steroidogenesis in MA-10 mouse Leydig tumor cells. Int J Biochem Cell Biol, 2005. 37(1): p. 214-23.
34. Ng, T.B. and H.X. Wang, Pharmacological actions of Cordyceps, a prized folk medicine. J Pharm Pharmacol, 2005. 57(12): p. 1509-19.
35. Cunningham, K.G., W. Manson, F.S. Spring, and S.A. Hutchinson, Cordycepin, a metabolic product isolated from cultures of Cordyceps militaris (Linn.) Link. Nature, 1950. 166(4231): p. 949.
36. Zeevi, M., J.R. Nevins, and J.E. Darnell, Jr., Newly formed mRNA lacking polyadenylic acid enters the cytoplasm and the polyribosomes but has a shorter half-life in the absence of polyadenylic acid. Mol Cell Biol, 1982. 2(5): p. 517-25.
37. Paterson, R.R., Cordyceps - A traditional Chinese medicine and another fungal therapeutic biofactory? Phytochemistry, 2008. 69(7): p. 1469-95.
38. Poon SL, H.B., The effect of cordycepin on steroidogenesis on steroidogenesis in normal mouse Leydig cells., in Society for the Study of Reproduction, 38th annual meeting. 2005: Quebec City, Quebec, Canada.
39. Pan, B.-S., The Mechanism of cordycepin-induced steroidogenesis in MA-10 mouse Leydig Tumor Cells, in Department of Cell Biology and Anatomy. 2007, National Cheng Kung University: Tainan.
40. Yang, H.Y., S.F. Leu, Y.K. Wang, C.S. Wu, and B.M. Huang, Cordyceps sinensis mycelium induces MA-10 mouse Leydig tumor cell apoptosis by activating the caspase-8 pathway and suppressing the NF-kappaB pathway. Arch Androl, 2006. 52(2): p. 103-10.
41. Wu, W.C., J.R. Hsiao, Y.Y. Lian, C.Y. Lin, and B.M. Huang, The apoptotic effect of cordycepin on human OEC-M1 oral cancer cell line. Cancer Chemother Pharmacol, 2007. 60(1): p. 103-11.
42. Lin, C.-Y., The apoptotic effect of cordycepin on MA-10 mouse Leydig tumor cell line, in Department of Cell Biology and Anatomy. 2006, National Cheng Kung University: Tainan.
43. Wiebe, J.P., Progesterone metabolites in breast cancer. Endocr Relat Cancer, 2006. 13(3): p. 717-38.
44. Bu, S.Z., D.L. Yin, X.H. Ren, L.Z. Jiang, Z.J. Wu, Q.R. Gao, and G. Pei, Progesterone induces apoptosis and up-regulation of p53 expression in human ovarian carcinoma cell lines. Cancer, 1997. 79(10): p. 1944-50.
45. Material Safety Data Sheet of cordycepin. CORDYCEPIN CRYSTALLINE 2006 [cited; Available from: http://www.sigmaaldrich.com/catalog/search/ProductDetail/SIGMA/C3394.
46. Huang, B.M., D.M. Stocco, P.H. Li, H.Y. Yang, C.M. Wu, and R.L. Norman, Corticotropin-releasing hormone stimulates the expression of the steroidogenic acute regulatory protein in MA-10 mouse cells. Biol Reprod, 1997. 57(3): p. 547-51.
47. Salva, A., G.R. Klinefelter, and M.P. Hardy, Purification of rat leydig cells: increased yields after unit-gravity sedimentation of collagenase-dispersed interstitial cells. J Androl, 2001. 22(4): p. 665-71.
48. Klinefelter, G.R., P.F. Hall, and L.L. Ewing, Effect of luteinizing hormone deprivation in situ on steroidogenesis of rat Leydig cells purified by a multistep procedure. Biol Reprod, 1987. 36(3): p. 769-83.
49. Huang, B.M., D.M. Stocco, and R.L. Norman, The cellular mechanisms of corticotropin-releasing hormone (CRH)-stimulated steroidogenesis in mouse Leydig cells are similar to those for LH. J Androl, 1997. 18(5): p. 528-34.
50. Bradford, M.M., A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem, 1976. 72: p. 248-54.
51. Resko, J.A., A. Malley, D. Begley, and D.L. Hess, Radioimmunoassay of testosterone during fetal development of the rhesus monkey. Endocrinology, 1973. 93(1): p. 156-61.
52. Yalow, R.S., Radioimmunoassay methodology: application to problems of heterogeneity of peptide hormones. Pharmacol Rev, 1973. 25(2): p. 161-78.
53. Yalow, R.S., Radioimmunoassay. Annu Rev Biophys Bioeng, 1980. 9: p. 327-45.
54. Carmichael, J., W.G. DeGraff, A.F. Gazdar, J.D. Minna, and J.B. Mitchell, Evaluation of a tetrazolium-based semiautomated colorimetric assay: assessment of chemosensitivity testing. Cancer Res, 1987. 47(4): p. 936-42.
55. Lowry, O.H., N.J. Rosebrough, A.L. Farr, and R.J. Randall, Protein measurement with the Folin phenol reagent. J Biol Chem, 1951. 193(1): p. 265-75.
56. Tamura, M., Y. Nakagawa, H. Shimizu, N. Yamada, T. Miyano, and H. Miyazaki, Cellular functions of mitogen-activated protein kinases and protein tyrosine phosphatases in ovarian granulosa cells. J Reprod Dev, 2004. 50(1): p. 47-55.
57. Rocha, A., I. Azevedo, and R. Soares, Progesterone sensitizes breast cancer MCF7 cells to imatinib inhibitory effects. J Cell Biochem, 2008. 103(2): p. 607-14.
58. Murdoch, W.J., E.A. Van Kirk, D.D. Isaak, and Y. Shen, Progesterone facilitates cisplatin toxicity in epithelial ovarian cancer cells and xenografts. Gynecol Oncol, 2008.
59. Lee, P.A. and M.T. Coughlin, Leydig cell function after cryptorchidism: evidence of the beneficial result of early surgery. J Urol, 2002. 167(4): p. 1824-7.
60. Wang, C., A. Leung, and A.P. Sinha-Hikim, Reproductive aging in the male brown-Norway rat: a model for the human. Endocrinology, 1993. 133(6): p. 2773-81.
61. Chen, H., M.P. Hardy, I. Huhtaniemi, and B.R. Zirkin, Age-related decreased Leydig cell testosterone production in the brown Norway rat. J Androl, 1994. 15(6): p. 551-7.
62. Pakarainen, T., F.P. Zhang, S. Makela, M. Poutanen, and I. Huhtaniemi, Testosterone replacement therapy induces spermatogenesis and partially restores fertility in luteinizing hormone receptor knockout mice. Endocrinology, 2005. 146(2): p. 596-606.
63. Spaliviero, J.A., M. Jimenez, C.M. Allan, and D.J. Handelsman, Luteinizing hormone receptor-mediated effects on initiation of spermatogenesis in gonadotropin-deficient (hpg) mice are replicated by testosterone. Biol Reprod, 2004. 70(1): p. 32-8.
64. Christensen, A.K. and K.C. Peacock, Increase in Leydig cell number in testes of adult rats treated chronically with an excess of human chorionic gonadotropin. Biol Reprod, 1980. 22(2): p. 383-91.
65. Chemes, H.E., M.A. Rivarola, and C. Bergada, Effect of HCG on the interstitial cells and androgen production in the immature rat testis. J Reprod Fertil, 1976. 46(2): p. 279-82.
66. Ralevic, V. and G. Burnstock, Receptors for purines and pyrimidines. Pharmacol Rev, 1998. 50(3): p. 413-92.
67. Zhao, Z., S. Ravid, and K. Ravid, Chromosomal mapping of the mouse A3 adenosine receptor gene, Adora3. Genomics, 1995. 30(1): p. 118-9.
68. Yoshikawa, N., S. Yamada, C. Takeuchi, S. Kagota, K. Shinozuka, M. Kunitomo, and K. Nakamura, Cordycepin (3'-deoxyadenosine) inhibits the growth of B16-BL6 mouse melanoma cells through the stimulation of adenosine A(3) receptor followed by glycogen synthase kinase-3beta activation and cyclin D (1) suppression. Naunyn Schmiedebergs Arch Pharmacol, 2007.
69. Lukyanenko, Y.O., A.M. Carpenter, D.E. Brigham, D.M. Stocco, and J.C. Hutson, Regulation of Leydig cells through a steroidogenic acute regulatory protein-independent pathway by a lipophilic factor from macrophages. J Endocrinol, 1998. 158(2): p. 267-75.
70. King, S.R., A.A. Matassa, E.K. White, L.P. Walsh, Y. Jo, R.M. Rao, D.M. Stocco, and M.E. Reyland, Oxysterols regulate expression of the steroidogenic acute regulatory protein. J Mol Endocrinol, 2004. 32(2): p. 507-17.
71. Gunnarsson, D., P. Leffler, E. Ekwurtzel, G. Martinsson, K. Liu, and G. Selstam, Mono-(2-ethylhexyl) phthalate stimulates basal steroidogenesis by a cAMP-independent mechanism in mouse gonadal cells of both sexes. Reproduction, 2008. 135(5): p. 693-703.
72. Jo, Y., S.R. King, S.A. Khan, and D.M. Stocco, Involvement of protein kinase C and cyclic adenosine 3',5'-monophosphate-dependent kinase in steroidogenic acute regulatory protein expression and steroid biosynthesis in Leydig cells. Biol Reprod, 2005. 73(2): p. 244-55.
73. Morris, J.K. and J.S. Richards, Luteinizing hormone induces prostaglandin endoperoxide synthase-2 and luteinization in vitro by A-kinase and C-kinase pathways. Endocrinology, 1995. 136(4): p. 1549-58.
74. Hirakawa, T., C. Galet, and M. Ascoli, MA-10 cells transfected with the human lutropin/choriogonadotropin receptor (hLHR): a novel experimental paradigm to study the functional properties of the hLHR. Endocrinology, 2002. 143(3): p. 1026-35.
75. Hirakawa, T. and M. Ascoli, The lutropin/choriogonadotropin receptor-induced phosphorylation of the extracellular signal-regulated kinases in leydig cells is mediated by a protein kinase a-dependent activation of ras. Mol Endocrinol, 2003. 17(11): p. 2189-200.
76. Manna, P.R., S.P. Chandrala, S.R. King, Y. Jo, R. Counis, I.T. Huhtaniemi, and D.M. Stocco, Molecular mechanisms of insulin-like growth factor-I mediated regulation of the steroidogenic acute regulatory protein in mouse leydig cells. Mol Endocrinol, 2006. 20(2): p. 362-78.
77. Gyles, S.L., C.J. Burns, B.J. Whitehouse, D. Sugden, P.J. Marsh, S.J. Persaud, and P.M. Jones, ERKs regulate cyclic AMP-induced steroid synthesis through transcription of the steroidogenic acute regulatory (StAR) gene. J Biol Chem, 2001. 276(37): p. 34888-95.
78. Lopez-Ilasaca, M., Signaling from G-protein-coupled receptors to mitogen-activated protein (MAP)-kinase cascades. Biochem Pharmacol, 1998. 56(3): p. 269-77.
79. Das, S., E.T. Maizels, D. DeManno, E. St Clair, S.A. Adam, and M. Hunzicker-Dunn, A stimulatory role of cyclic adenosine 3',5'-monophosphate in follicle-stimulating hormone-activated mitogen-activated protein kinase signaling pathway in rat ovarian granulosa cells. Endocrinology, 1996. 137(3): p. 967-74.
80. Tajima, K., A. Dantes, Z. Yao, K. Sorokina, F. Kotsuji, R. Seger, and A. Amsterdam, Down-regulation of steroidogenic response to gonadotropins in human and rat preovulatory granulosa cells involves mitogen-activated protein kinase activation and modulation of DAX-1 and steroidogenic factor-1. J Clin Endocrinol Metab, 2003. 88(5): p. 2288-99.
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