GnRH Receptors in Cancer: From Cell Biology to Novel Targeted Therapeutic Strategies

The crucial role of pituitary GnRH receptors (GnRH-R) in the control of reproductive functions is well established. These receptors are the target of GnRH agonists (through receptor desensitization) and antagonists (through receptor blockade) for the treatment of steroid-dependent pathologies, inclu...

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Published inEndocrine reviews Vol. 33; no. 5; pp. 784 - 811
Main Authors Limonta, Patrizia, Marelli, Marina Montagnani, Mai, Stefania, Motta, Marcella, Martini, Luciano, Moretti, Roberta M
Format Journal Article
LanguageEnglish
Published Bethesda, MD Endocrine Society 01.10.2012
Copyright by The Endocrine Society
Subjects
Antineoplastic Agents, Hormonal - therapeutic use
Biological and medical sciences
Fundamental and applied biological sciences. Psychology
Hormone Antagonists - therapeutic use
Humans
Neoplasms - drug therapy
Neoplasms - metabolism
Receptors, LHRH - agonists
Receptors, LHRH - antagonists & inhibitors
Receptors, LHRH - metabolism
Signal Transduction - physiology
Vertebrates: endocrinology
Hypothalamic hormone
Cell biology
Gonadotropin RH
Review
Malignant tumor
Hormone releasing factor
Cancer
Biological receptor
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Abstract The crucial role of pituitary GnRH receptors (GnRH-R) in the control of reproductive functions is well established. These receptors are the target of GnRH agonists (through receptor desensitization) and antagonists (through receptor blockade) for the treatment of steroid-dependent pathologies, including hormone-dependent tumors. It has also become increasingly clear that GnRH-R are expressed in cancer tissues, either related (i.e. prostate, breast, endometrial, and ovarian cancers) or unrelated (i.e. melanoma, glioblastoma, lung, and pancreatic cancers) to the reproductive system. In hormone-related tumors, GnRH-R appear to be expressed even when the tumor has escaped steroid dependence (such as castration-resistant prostate cancer). These receptors are coupled to a Gαi-mediated intracellular signaling pathway. Activation of tumor GnRH-R by means of GnRH agonists elicits a strong antiproliferative, antimetastatic, and antiangiogenic (more recently demonstrated) activity. Interestingly, GnRH antagonists have also been shown to elicit a direct antitumor effect; thus, these compounds behave as antagonists of GnRH-R at the pituitary level and as agonists of the same receptors expressed in tumors. According to the ligand-induced selective-signaling theory, GnRH-R might assume various conformations, endowed with different activities for GnRH analogs and with different intracellular signaling pathways, according to the cell context. Based on these consistent experimental observations, tumor GnRH-R are now considered a very interesting candidate for novel molecular, GnRH analog-based, targeted strategies for the treatment of tumors expressing these receptors. These agents include GnRH agonists and antagonists, GnRH analog-based cytotoxic (i.e. doxorubicin) or nutraceutic (i.e. curcumin) hybrids, and GnRH-R-targeted nanoparticles delivering anticancer compounds.
AbstractList The crucial role of pituitary GnRH receptors (GnRH-R) in the control of reproductive functions is well established. These receptors are the target of GnRH agonists (through receptor desensitization) and antagonists (through receptor blockade) for the treatment of steroid-dependent pathologies, including hormone-dependent tumors. It has also become increasingly clear that GnRH-R are expressed in cancer tissues, either related (i.e. prostate, breast, endometrial, and ovarian cancers) or unrelated (i.e. melanoma, glioblastoma, lung, and pancreatic cancers) to the reproductive system. In hormone-related tumors, GnRH-R appear to be expressed even when the tumor has escaped steroid dependence (such as castration-resistant prostate cancer). These receptors are coupled to a G(αi)-mediated intracellular signaling pathway. Activation of tumor GnRH-R by means of GnRH agonists elicits a strong antiproliferative, antimetastatic, and antiangiogenic (more recently demonstrated) activity. Interestingly, GnRH antagonists have also been shown to elicit a direct antitumor effect; thus, these compounds behave as antagonists of GnRH-R at the pituitary level and as agonists of the same receptors expressed in tumors. According to the ligand-induced selective-signaling theory, GnRH-R might assume various conformations, endowed with different activities for GnRH analogs and with different intracellular signaling pathways, according to the cell context. Based on these consistent experimental observations, tumor GnRH-R are now considered a very interesting candidate for novel molecular, GnRH analog-based, targeted strategies for the treatment of tumors expressing these receptors. These agents include GnRH agonists and antagonists, GnRH analog-based cytotoxic (i.e. doxorubicin) or nutraceutic (i.e. curcumin) hybrids, and GnRH-R-targeted nanoparticles delivering anticancer compounds.
The crucial role of pituitary GnRH receptors (GnRH-R) in the control of reproductive functions is well established. These receptors are the target of GnRH agonists (through receptor desensitization) and antagonists (through receptor blockade) for the treatment of steroid-dependent pathologies, including hormone-dependent tumors. It has also become increasingly clear that GnRH-R are expressed in cancer tissues, either related (i.e. prostate, breast, endometrial, and ovarian cancers) or unrelated (i.e. melanoma, glioblastoma, lung, and pancreatic cancers) to the reproductive system. In hormone-related tumors, GnRH-R appear to be expressed even when the tumor has escaped steroid dependence (such as castration-resistant prostate cancer). These receptors are coupled to a Gαi-mediated intracellular signaling pathway. Activation of tumor GnRH-R by means of GnRH agonists elicits a strong antiproliferative, antimetastatic, and antiangiogenic (more recently demonstrated) activity. Interestingly, GnRH antagonists have also been shown to elicit a direct antitumor effect; thus, these compounds behave as antagonists of GnRH-R at the pituitary level and as agonists of the same receptors expressed in tumors. According to the ligand-induced selective-signaling theory, GnRH-R might assume various conformations, endowed with different activities for GnRH analogs and with different intracellular signaling pathways, according to the cell context. Based on these consistent experimental observations, tumor GnRH-R are now considered a very interesting candidate for novel molecular, GnRH analog-based, targeted strategies for the treatment of tumors expressing these receptors. These agents include GnRH agonists and antagonists, GnRH analog-based cytotoxic (i.e. doxorubicin) or nutraceutic (i.e. curcumin) hybrids, and GnRH-R-targeted nanoparticles delivering anticancer compounds.
Author Moretti, Roberta M
Motta, Marcella
Mai, Stefania
Martini, Luciano
Limonta, Patrizia
Marelli, Marina Montagnani
AuthorAffiliation Sezione di Biomedicina ed Endocrinologia, Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, 20133 Milano, Italy
AuthorAffiliation_xml – name: Sezione di Biomedicina ed Endocrinologia, Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, 20133 Milano, Italy
Author_xml – sequence: 1
  givenname: Patrizia
  surname: Limonta
  fullname: Limonta, Patrizia
  email: patrizia.limonta@unimi.it
– sequence: 2
  givenname: Marina Montagnani
  surname: Marelli
  fullname: Marelli, Marina Montagnani
– sequence: 3
  givenname: Stefania
  surname: Mai
  fullname: Mai, Stefania
– sequence: 4
  givenname: Marcella
  surname: Motta
  fullname: Motta, Marcella
– sequence: 5
  givenname: Luciano
  surname: Martini
  fullname: Martini, Luciano
– sequence: 6
  givenname: Roberta M
  surname: Moretti
  fullname: Moretti, Roberta M
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Cell biology
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Malignant tumor
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Biological receptor
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Chen (2020071612233190300_B140) 2008; 51
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Snippet The crucial role of pituitary GnRH receptors (GnRH-R) in the control of reproductive functions is well established. These receptors are the target of GnRH...
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wolterskluwer
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SubjectTerms Antineoplastic Agents, Hormonal - therapeutic use
Biological and medical sciences
Fundamental and applied biological sciences. Psychology
Hormone Antagonists - therapeutic use
Humans
Neoplasms - drug therapy
Neoplasms - metabolism
Receptors, LHRH - agonists
Receptors, LHRH - antagonists & inhibitors
Receptors, LHRH - metabolism
Signal Transduction - physiology
Vertebrates: endocrinology
Title GnRH Receptors in Cancer: From Cell Biology to Novel Targeted Therapeutic Strategies
URI http://dx.doi.org/10.1210/er.2012-1014
http://ovidsp.ovid.com/ovidweb.cgi?T=JS&NEWS=n&CSC=Y&PAGE=fulltext&D=ovft&AN=00003599-201210000-00004
https://www.ncbi.nlm.nih.gov/pubmed/22778172
https://search.proquest.com/docview/1095452842
Volume 33
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