title: Prolyl Hydroxylase 3 Attenuates MCL-1-Mediated ATP Production to Suppress the Metastatic Potential of Colorectal Cancer Cells.
abstract: Hypoxia is a common feature of solid tumors. Prolyl hydroxylase enzymes (PHD1-3) are molecular oxygen sensors that regulate hypoxia-inducible factor activity, but their functions in metastatic disease remain unclear. Here, we assessed the significance of PHD enzymes during the metastatic spread of colorectal cancer. PHD expression analysis in 124 colorectal cancer patients revealed that reduced tumoral expression of PHD3 correlated with increased frequency of distant metastases and poor outcome. Tumorigenicity and metastatic potential of colorectal tumor cells over and underexpressing PHD3 were investigated in orthotopic and heterotopic tumor models. PHD3 overexpression in a syngeneic tumor model resulted in fewer liver metastases, whereas PHD3 knockdown induced tumor spread. The migration of PHD3-overexpressing tumor cells was also attenuated in vitro Conversely, migratory potential and colony formation were enhanced in PHD3-deficient cells, and this phenotype was associated with enhanced mitochondrial ATP production. Furthermore, the effects of PHD3 deficiency were accompanied by increased mitochondrial expression of the BCL-2 family member, member myeloid cell leukemia sequence 1 (MCL-1), and could be reversed by simultaneous inhibition of MCL-1. MCL-1 protein expression was likewise enhanced in human colorectal tumors expressing low levels of PHD3. Therefore, we demonstrate that downregulation of PHD3 augments metastatic spread in human colorectal cancer and identify MCL-1 as a novel downstream effector of oxygen sensing. Importantly, these findings offer new insight into the possible, context-specific deleterious effects of pharmacologic PHD inhibition. Cancer Res; 76(8); 2219-30. ©2016 AACR.
authors.affiliation: Department of General, Visceral and Transplantation Surgery, Heidelberg University Hospital, Heidelberg, Germany.
authors.forename: Praveenkumar
authors.initials: P
authors.lastname: Radhakrishnan
authors.affiliation: Department of General, Visceral and Transplantation Surgery, Heidelberg University Hospital, Heidelberg, Germany.
authors.forename: Nadine
authors.initials: N
authors.lastname: Ruh
authors.affiliation: Department of General, Visceral and Transplantation Surgery, Heidelberg University Hospital, Heidelberg, Germany.
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Harnoss
authors.affiliation: Department of General, Visceral and Transplantation Surgery, Heidelberg University Hospital, Heidelberg, Germany.
authors.forename: Judit
authors.initials: J
authors.lastname: Kiss
authors.affiliation: Department of General, Visceral and Transplantation Surgery, Heidelberg University Hospital, Heidelberg, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Mollenhauer
authors.affiliation: Department of Medical Oncology, Internal Medicine VI, National Center for Tumor Diseases, Heidelberg University Hospital, Heidelberg, Germany.
authors.forename: Anna-Lena
authors.initials: AL
authors.lastname: Scherr
authors.affiliation: Department of General, Visceral and Transplantation Surgery, Heidelberg University Hospital, Heidelberg, Germany.
authors.forename: Lisa K
authors.initials: LK
authors.lastname: Platzer
authors.affiliation: Department of General, Visceral and Transplantation Surgery, Heidelberg University Hospital, Heidelberg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Schmidt
authors.affiliation: Department of Medical Oncology, Internal Medicine VI, National Center for Tumor Diseases, Heidelberg University Hospital, Heidelberg, Germany.
authors.forename: Klaus
authors.initials: K
authors.lastname: Podar
authors.affiliation: St. Jude Children's Research Hospital, Cell & Molecular Biology, Memphis, Tennessee.
authors.forename: Joseph T
authors.initials: JT
authors.lastname: Opferman
authors.affiliation: Department of General, Visceral and Transplantation Surgery, Heidelberg University Hospital, Heidelberg, Germany. Department of Visceral, Thoracic and Vascular Surgery, Dresden University Hospital, Dresden, Germany.
authors.forename: Juergen
authors.initials: J
authors.lastname: Weitz
authors.affiliation: Department of Medical Oncology, Internal Medicine VI, National Center for Tumor Diseases, Heidelberg University Hospital, Heidelberg, Germany.
authors.forename: Henning
authors.initials: H
authors.lastname: Schulze-Bergkamen
authors.affiliation: Department of Medical Oncology, Internal Medicine VI, National Center for Tumor Diseases, Heidelberg University Hospital, Heidelberg, Germany.
authors.forename: Bruno C
authors.initials: BC
authors.lastname: Koehler
authors.affiliation: Department of General, Visceral and Transplantation Surgery, Heidelberg University Hospital, Heidelberg, Germany.
authors.forename: Alexis
authors.initials: A
authors.lastname: Ulrich
authors.affiliation: Department of General, Visceral and Transplantation Surgery, Heidelberg University Hospital, Heidelberg, Germany. m.schneider@uni-heidelberg.de.
authors.forename: Martin
authors.initials: M
authors.lastname: Schneider
mesh_terms: D000255:Adenosine Triphosphate / Q000096:biosynthesis*; D000818:Animals; D015179:Colorectal Neoplasms / Q000473:pathology*; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000502:physiology*; D009362:Neoplasm Metastasis; D064828:Prolyl Hydroxylases / Q000378:metabolism*
chemical_list: C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D000255:Adenosine Triphosphate; D064828:Prolyl Hydroxylases