Inhibition of HIF Prolyl Hydroxylase-2 Blocks Tumor Growth in Mice through the Antiproliferative Activity of TGFβ

• Published in: Cancer research (Chicago, Ill.) Vol. 71; no. 9; pp. 3306 - 3316
• Main Authors: KLOTZSCHE-VON AMELN, Anne, MUSCHTER, Antje, MAMLOUK, Soulafa, KALUCKA, Joanna, PRADE, Ina, FRANKE, Kristin, REZAEI, Maryam, POITZ, David M, BREIER, Georg, WIELOCKX, Ben
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01-05-2011
• Subjects: Animals; Antineoplastic agents; Biological and medical sciences; Bone Neoplasms - enzymology; Bone Neoplasms - metabolism; Bone Neoplasms - pathology; Cell Growth Processes - physiology; Cell Line, Tumor; Female; Gene Knockdown Techniques; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Hypoxia-Inducible Factor-Proline Dioxygenases; Medical sciences; Melanoma, Experimental - enzymology; Melanoma, Experimental - metabolism; Melanoma, Experimental - pathology; Mice; Mice, Inbred C3H; Mice, Inbred C57BL; Neoplasms, Experimental - enzymology; Neoplasms, Experimental - metabolism; Neoplasms, Experimental - pathology; Osteosarcoma - enzymology; Osteosarcoma - metabolism; Osteosarcoma - pathology; Pharmacology. Drug treatments; Procollagen-Proline Dioxygenase - antagonists & inhibitors; Procollagen-Proline Dioxygenase - genetics; Procollagen-Proline Dioxygenase - metabolism; RNA, Small Interfering - administration & dosage; RNA, Small Interfering - genetics; Transforming Growth Factor beta - metabolism; Tumors; Antineoplastic agent; Transforming growth factor β; Rodentia; Malignant tumor; Biological activity; Vertebrata; Mammalia; Tumor growth; Mouse; Animal; Inhibitor; Inhibition; Cancer
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-10-3838

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.