Endocrine Abstracts

Pituitary tumors are most usual intracranial tumors, displaying hormonal hyper-secretion with in some cases a sustained cell proliferation. The somatotroph adenomas are characterised by a GH hypersecretion. The current treatments are based on somatostatinergic or dopaminergic agonists. Unfortunately, there is steel 50% of patients, which remain insensitive to these treatments. The aim of our work is to find a pharmacological alternative to treat the patients resistant to the current therapies. Ghrelin stimulate pituitary GH release in vivo trough GHS-R1a activation. Interestingly, this receptor not only transduces signal via Ghrelin binding, but also through an unusual high constitutive activity. Noteworthy, human somatotroph adenomas expressed a high level of GHS-R1a at both mRNA and protein level. We actually assess the implication of this constitutive activity in the tumorigenesis of the somatotroph adenomas.

Firstly we demonstrated GHS-R1a functionality through its capacity to fixe endogenous ligand, performing Fluo-ghrelin tracking. Then we showed that treatment of human somatotroph adenomas primary cultures, with the GHS-R1a inverse agonist (modified substance P (MSP)), induced a dose dependent decrease of GH secretion. Apoptotic cell death could also be promoted by MSP treatment. To foremost investigate the transduction mechanisms underlying these results, we developed, from GH4C1 (rat somato-lactotroph tumoral cell line), stable cell clones overexpressing human GHS-R1a (named MYST-Rg). Interestingly, hGHS-R1a overexpressing cells proliferate faster than empty vector transfected cells (named MYST-mock). They also exhibit relatively high basal activation of the IP3 pathway. GHS-R1a full agonist (MK 677) strengthens basal IP3 pathway activation of MYST-Rg cells and mobilizes intracellular Ca²⁺. Noteworthy, the basal IP3 pathway activation can be lessened by MSP treatment.

Thus, MSP could be a useful alternative to the current therapies of somatotroph adenomas as it inhibits constitutive IP-3 signalling, known as a significant hormonal release pathway, and promote apoptotic cell death.