title: Inhibition of HIF prolyl hydroxylase-2 blocks tumor growth in mice through the antiproliferative activity of TGFβ.
abstract: Virtually all solid tumors are dependent on a vascular network to provide them with the right amount of nutrients and oxygen. In that sense, low oxygen tension or hypoxia leads to an adaptive response that is transcriptionally regulated by the hypoxia-inducible factors (HIF), which are tightly controlled by the HIF prolyl hydroxylases (PHD). In this study, we show that inhibition of the oxygen sensor PHD2 in tumor cells stimulates vessel formation but paradoxically results in a profound reduction of tumor growth. This effect relies on the antiproliferative nature of the TGFβ signaling pathway, in a largely HIF-independent manner. Moreover, our findings reveal that PHD2 has an essential function in controlling the dual nature of TGFβ during tumorigenesis and may offer an alternative opportunity for anticancer therapy.
authors: Department of Pathology, Dresden University of Technology, Dresden, Saxony, Germany.
authors: Anne
authors: A
authors: Klotzsche-von Ameln
authors: Antje
authors: A
authors: Muschter
authors: Soulafa
authors: S
authors: Mamlouk
authors: Joanna
authors: J
authors: Kalucka
authors: Ina
authors: I
authors: Prade
authors: Kristin
authors: K
authors: Franke
authors: Maryam
authors: M
authors: Rezaei
authors: David M
authors: DM
authors: Poitz
authors: Georg
authors: G
authors: Breier
authors: Ben
authors: B
authors: Wielockx
mesh_terms: D000818:Animals; D001859:Bone Neoplasms / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D005260:Female; D055785:Gene Knockdown Techniques; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D008546:Melanoma, Experimental / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D009374:Neoplasms, Experimental / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology*; D012516:Osteosarcoma / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D011393:Procollagen-Proline Dioxygenase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000378:metabolism*
chemical_list: C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D034741:RNA, Small Interfering; D016212:Transforming Growth Factor beta; D011393:Procollagen-Proline Dioxygenase; C490189:Egln1 protein, mouse; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases