Endocrine Abstracts (2009) 20 P565

Expression and regulation of HIF-1[alpha] and RSUME in murine and human pituitary tumor cells

Bing Shan1, Marily Theodoropoulou1, Michael Buchfelder2, Walter Rachinger3, Marco Losa4, Günter Stalla1, Eduardo Arzt5 & Ulrich Renner1

1Max Planck Institute of Psychiatry, Munich, Germany; 2University of Erlangen-Nuremburg, Erlangen, Germany; 3University of Munich, Munich, Germany; 4Istituto San Raffaele, Milano, Italy; 5FCEN-Universidad de Buenos Aires, Buenos Aires, Argentina.

Hypoxia inducible factor-1alpha (HIF-1α) is a transcription factor regulating expression of many genes related to oxygen homeostasis in response to hypoxic stress. RSUME is a sumoylation enhancer, which was recently cloned from a pituitary cell line with an increased tumorigenic and angiogenic potential. It has been shown that RSMUE is induced by hypoxia and enhances the sumoylation of HIF-1α. Although many studies demonstrated that the level of HIF-1α is remarkably high in some kinds of tumors to increase oxygen availability by promoting tumor neovascularization, the situation in human pituitary tumors is still unclear. The aim of our work is to investigate the expression of HIF-1α in adenomatous pituitaries and the relationship between HIF-1α and RSUME. In our preliminary study, samples of three corticotrophic adenomas, five somatotrophic adenomas and two prolactinomas were detected by immunohistochemistry, and the results have shown that some of them have significantly higher levels of HIF-1α, compared with normal pituitaries. In order to investigate the regulation of HIF-1α and RSUME under hypoxic condition, we stimulated mouse pituitary tumor cell lines (TtT/GF and AtT20) and human none function pituitary adenoma primary cell cultures with cobalt chloride, which is a well-known hypoxia-mimicking agent. In all of the cell cultures, a time and dose dependent increase of HIF-1α was observed, and this could be suppressed with RSUME siRNA in both TtT/GF and AtT20 cell lines. VEGF was time and dose dependently stimulated in TtT/GF but not in AtT20 cells. By RT-PCR it was shown in both cell lines that cobalt chloride treatment enhanced RSUME mRNA expression, which could be inhibited by siRNA, and 45% human pituitary tumor samples have significantly higher RSUME mRNA expression in 33 samples compared with 4 normal human pituitaries. Our preliminary findings suggest that the level of HIF-1α increases in some pituitary adenomas and RSUME stabilizes HIF-1α in some pituitary cell lines under hypoxia mimicking condition. The co-localization of HIF-1α and RSUME in human pituitary tumors is being studied and more evidences need to be provided to elucidate that RSUME stabilizes HIF-1α in pituitary tumors, which probably gives a new access to control pituitary tumor development.

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