Abstract
The treatment of growth hormone (GH)- and prolactin (PRL)-secreting tumors resistant to current therapeutic molecules (somatostatin and dopamine analogues) remains challenging. To target these tumors specifically, we chose to inactivate a gene coding for a crucial factor in cell proliferation and hormonal regulation, specifically expressed in pituitary, by using a dominant-negative form of this gene involved in human pituitary deficiencies: transcription factor Pit-1 (POU1F1) mutated on arginine 271 to tryptophan (R271W). After lentiviral transfer, the effect of R271W was studied in vitro on human tumoral somatotroph and lactotroph cells and on the murine mammosomatotroph cell line GH4C1 and in vivo on GH4C1 subcutaneous xenografts in nude mice. R271W induced a decrease in GH and PRL hypersecretion by controlling the transcription of the corresponding hormones. This mutant decreased cell viability by an apoptotic mechanism and in vivo blocked the tumoral growth and GH secretion of xenografts obtained after transplantation of GH4C1 expressing mutant R271W. The strategy of using a dominant-negative form of a main factor controlling cell proliferation and hormonal secretion, and exclusively expressed in pituitary, seems promising for the gene therapy of human pituitary tumors and may be translated to other types of tumors maintaining some differentiation features.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenoma / genetics
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Adenoma / metabolism
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Adenoma / therapy
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Animals
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Arginine / genetics
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Arginine / metabolism
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Blotting, Western
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Cell Death
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Cell Proliferation
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Cell Survival
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Cell Transplantation / methods
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Female
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Gene Transfer Techniques
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Genetic Therapy / methods*
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Genetic Vectors / administration & dosage
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Genetic Vectors / genetics
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Genetic Vectors / metabolism
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Genetic Vectors / therapeutic use
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Green Fluorescent Proteins / genetics
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Green Fluorescent Proteins / metabolism
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Growth Hormone-Secreting Pituitary Adenoma / genetics
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Growth Hormone-Secreting Pituitary Adenoma / metabolism
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Growth Hormone-Secreting Pituitary Adenoma / therapy
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Human Growth Hormone / analysis
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Human Growth Hormone / metabolism
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Humans
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Lentivirus / genetics
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Lentivirus / metabolism
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Mice
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Mice, Nude
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Pituitary Neoplasms / genetics
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Pituitary Neoplasms / metabolism
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Pituitary Neoplasms / therapy
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Prolactin / analysis
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Prolactin / blood
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Prolactin / metabolism*
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Prolactinoma / genetics
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Prolactinoma / therapy
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Transcription Factor Pit-1 / genetics
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Transcription Factor Pit-1 / metabolism*
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Transcriptional Activation*
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Transgenes
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Tryptophan / genetics
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Tryptophan / metabolism
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Tumor Cells, Cultured
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Xenograft Model Antitumor Assays
Substances
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POU1F1 protein, human
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Transcription Factor Pit-1
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enhanced green fluorescent protein
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Human Growth Hormone
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Green Fluorescent Proteins
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Tryptophan
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Prolactin
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Arginine