The CXCR4 antagonist AMD3100 suppresses hypoxia-mediated growth hormone production in GH3 rat pituitary adenoma cells

D Yoshida, K Koketshu, R Nomura, A Teramoto
Journal of Neuro-oncology 2010, 100 (1): 51-64
Pituitary adenomas produce the chemokine stromal cell-derived factor (SDF-1α/CXCL12) and its receptor, CXCR4. A recent study indicated that CXCL12 and CXCR4 are concomitantly up-regulated in hypoxia. The objective of this study was to analyze the molecular mechanism of hypoxia-mediated CXCR4 up-regulation and assess the effect of pharmacological inhibition of CXCR4 by the receptor blocker, AMD3100, on pituitary function. CXCR4 expression in pituitary adenoma tissues was determined by a tissue microarray analysis of 62 pituitary adenoma samples. CXCR4 expression was significantly elevated and positively correlated with Knosp grade in pituitary adenomas (P < 0.005), and was higher in macroadenoma and growth hormone (GH)-producing adenomas. Pre-operative serum GH levels were significantly correlated with CXCR4 levels in the microarray (P < 0.0001). The relative expression of genes/gene categories that were modulated by up-regulated CXCL12/CXCR4 signaling was determined by a comparative transcriptome analysis of wild-type and CXCR4-knockdown cells in normoxia and hypoxia using the rat GH-producing and prolactin-producing pituitary adenoma cell line, GH3. Real-time reverse transcriptase-polymerase chain reaction analysis (RT-PCR) showed that CXCR4 mRNA expression in GH3 cells was increased by hypoxia (1% oxygen), and a cDNA microarray analysis revealed that inhibin β-C expression was diminished. siRNA-mediated CXCR4 knockdown blocked the hypoxia-induced decrease in inhibin β-C mRNA expression, as did inhibition of CXCR4 activity with AMD3100. An ELISA study demonstrated that GH secretion by wild-type GH3 cells was moderately enhanced by hypoxia and further potentiated by exposure to recombinant SDF-1α/CXCL12 protein. Conversely, hypoxia-induced GH secretion was reduced in CXCR4-silenced cells and in cells treated with the CXCR4 antagonist, AMD3100, notwithstanding the presence of SDF-1α/CXCL12 protein. These latter observations reflect the failure of hypoxia to suppress expression of inhibin β-C in cells deficient in CXCR4 or in which CXCR4 signaling was blocked. Together, these results indicate that the SDF-1α/CXCL12-CXCR4 signaling pathway interfaces with the classical endocrine pathway to up-regulate GH production via suppression of inhibin β-C. Because it blocks CXCR4 and prevents hypoxia-induced down-regulation of inhibin β-C expression, AMD3100 has promise as a molecular-targeting agent in the treatment of GH-producing adenomas.

Full Text Links

Find Full Text Links for this Article


You are not logged in. Sign Up or Log In to join the discussion.

Related Papers

Remove bar
Read by QxMD icon Read

Save your favorite articles in one place with a free QxMD account.


Search Tips

Use Boolean operators: AND/OR

diabetic AND foot
diabetes OR diabetic

Exclude a word using the 'minus' sign

Virchow -triad

Use Parentheses

water AND (cup OR glass)

Add an asterisk (*) at end of a word to include word stems

Neuro* will search for Neurology, Neuroscientist, Neurological, and so on

Use quotes to search for an exact phrase

"primary prevention of cancer"
(heart or cardiac or cardio*) AND arrest -"American Heart Association"