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Estrogen receptors and intracellular signaling pathways involved in the regulation of cell proliferation of testicular cancer and castration-resistant prostate cancer


Testicular cancer has the one of the highest cure rates among all cancer. However, it has been observed, in addition to male infertility, the resistance to treatment in 30% of the patients with metastatic non-seminoma testicular cancer. There are many genes and signaling pathways associated with testicular cancer. Estrogens, their receptors (ESR1 and ESR2) and signaling pathways may play a role in the development and maintenance of these tumors. The understanding of the molecular mechanisms involved may reveal new therapeutic targets for the treatment. Thus, the aim of this study is to investigate the effects of 17²-estradiol (E2) and ESR1-selective agonist ( PPT ) and ESR2-selective agonist (DPN) in the expression and function of the transcription factor KLF-4 in NT2/D1 (embryonal carcinoma ) and TCAM-2 (seminoma) cells, as a model of testicular cancer. After the activation of ESR1 and/or ESR2, will be determined: i) the expression of the transcription factor KLF-4, ii ) the intracellular mechanisms involved in the stability of KLF - 4, as the proteins involved in its degradation p-VHL, ²TrCP and ERK1/2, iii ) the role of KLF-4 in the regulation of proteins involved in the cell cycle (Cyclin D1, D2 and E and p27KIP1) and iv) the role of KLF-4 in migration/invasion of the cell and the expression of TIMP2.Prostate cancer initially responds well to androgen-deprivation therapies, but the majority of tumors evolve from an androgen-sensitive to an androgen-independent form of the disease, also known as castration-resistant prostate cancer (CRPC). The molecular mechanisms that drive the progression of androgen-sensitive to CRPC are still not well understood. The estrogen may be involved in the development and maintenance of the CRPC. Thus, aim of this study is to investigate the effects of activation of the classic estrogen receptors ESR1 and ESR2 regulating of the expression and function of ²-catenin, the transcription factors KL-4 and ETV4 on the androgen-independent prostate cancer cell line PC-3 and DU145, used as a model of CRPC. After the activation of ESR1 and/or ESR2, will be determined: i) the expression and cellular localization of non-phosphorylated ²-catenin, KLF-4 and ETV4; ii) the binding of non-phosphorylated ²-catenin to the factor transcription TCF/LEF and expression of Cyclin D1 and D2 and the incorporation of [methyl-3H]thymidine; iii) the stability of the KLF-4 in the presence of the protein synthesis inhibitors cycloheximide and inhibitor of proteasome MG132; iv) regulation and involvement of ²TrCP and VHL with KLF-4 degradation, v) the function of ER-KLF-4 and ER- ETV4 on the expression of p27KIP1 , p57 and TIMP2 and the formation of clones and cell invasion . (AU)

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Scientific publications (6)
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
LOMBARDI, ANA PAOLA G.; CAVALHEIRO, RENAN P.; PORTO, CATARINA S.; VICENTE, CAROLINA M.. Estrogen Receptor Signaling Pathways Involved in Invasion and Colony Formation of Androgen-Independent Prostate Cancer Cells PC-3. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, v. 22, n. 3, . (17/16060-3, 14/05292-2)
LOMBARDI, ANA PAOLA G.; PISOLATO, RAISA; VICENTE, CAROLINA M.; LAZARI, MARIA FATIMA M.; LUCAS, THAIS F. G.; PORTO, CATARINA S.. Estrogen receptor beta (ER beta) mediates expression of beta-catenin and proliferation in prostate cancer cell line PC-3. Molecular and Cellular Endocrinology, v. 430, n. C, p. 12-24, . (08/56564-1, 14/05292-2)
SILVA, RAFAEL DE SOUZA; LOMBARDI, ANA PAOLA G.; DE SOUZA, DEBORAH SIMAO; VICENTE, CAROLINA M.; PORTO, CATARINA S.. Activation of estrogen receptor beta (ER beta) regulates the expression of N-cadherin, E-cadherin and beta-catenin in androgen-independent prostate cancer cells. INTERNATIONAL JOURNAL OF BIOCHEMISTRY & CELL BIOLOGY, v. 96, p. 40-50, . (14/05292-2)
LOMBARDI, ANA PAOLA G.; VICENTE, CAROLINA M.; PORTO, CATARINA S.. Estrogen Receptors Promote Migration, Invasion and Colony Formation of the Androgen-Independent Prostate Cancer Cells PC-3 Through beta-Catenin Pathway. FRONTIERS IN ENDOCRINOLOGY, v. 11, . (14/05292-2, 17/16060-3)
MACHERONI, CARLA; GAMEIRO LUCAS, THAIS FABIANA; PORTO, CATARINA SEGRETI. The role of estrogen receptors in rat Sertoli cells at different stages of development. HELIYON, v. 6, n. 11, . (14/05292-2)
SOUZA, DEBORAH S.; LOMBARDI, ANA PAOLA G.; VICENTE, CAROLINA M.; LUCAS, THAIS FABIANA G.; ERUSTES, ADOLFO G.; PEREIRA, GUSTAVO J. S.; PORTO, CATARINA S.. Estrogen receptors localization and signaling pathways in DU-145 human prostate cancer cells. Molecular and Cellular Endocrinology, v. 483, p. 11-23, . (14/05292-2, 17/16060-3)

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