title: Runx2-Smad signaling impacts the progression of tumor-induced bone disease.
abstract: Runx2, a master regulator of osteogenesis, is abnormally expressed in advanced prostate cancer. Here, we addressed Runx2 contribution to formation of prostate cancer-related osteolytic and osteoblastic bone lesions by mediating TGFβ/BMP signaling through direct interaction with Smads. Further, we examined involvement of the Runx2-Smad complex in mediating tumor growth and distal metastasis. To identify Runx2-Smad-specific mechanisms of prostate tumor activity in bone, we generated PC3 prostate cancer cell lines expressing Runx2-WT or one of two mutant proteins (Runx2-HTY and Runx2-ΔC) that each disrupt the Runx2-Smad interaction, either directly through a point mutation or by deletion of the functional C-terminus, respectively. Intratibial tumors generated from these cells revealed that Runx2-WT-expressing cells resulted in predominantly osteolytic disease, whereas cells expressing mutant proteins exhibited tumors with mixed osteolytic/osteoblastic lesions. Extent of bone loss and woven bone formation was assessed by radiography and micro-computed tomography. Bioluminescent imaging showed the presence of labeled prostate cancer cells in the lung at the latest time point examined, with Runx2-WT group exhibiting increased incidence of tumor cells in lung. Notably, disruption of the Runx2-Smad interaction significantly reduced incidence and size of lung tumors. Altered expression of Runx2 target genes involved in invasion, growth, adhesion and metastasis supported our findings. Thus, our studies demonstrate that Runx2 in prostate cancer cells plays a significant role in intratibial prostate cancer-related tumor growth and bone loss through mechanisms mediated by the Runx2-Smad signaling pathway. This work expands upon the potential importance of Runx2 as a therapeutic target in cancer.
authors: Department of Biochemistry, University of Vermont College of Medicine, Burlington, VT; Department of Cell Biology, University of Massachusetts Medical School, Worcester, MA.
authors: Xuhui
authors: X
authors: Zhang
authors: Jacqueline
authors: J
authors: Akech
authors: Gillian
authors: G
authors: Browne
authors: Stacey
authors: S
authors: Russell
authors: John J
authors: JJ
authors: Wixted
authors: Janet L
authors: JL
authors: Stein
authors: Gary S
authors: GS
authors: Stein
authors: Jane B
authors: JB
authors: Lian
mesh_terms: D000818:Animals; D001847:Bone Diseases / Q000209:etiology*; D045744:Cell Line, Tumor; D050659:Core Binding Factor Alpha 1 Subunit / Q000502:physiology*; D018450:Disease Progression; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics; D006801:Humans; D008297:Male; D051379:Mice; D053495:Osteopontin / Q000235:genetics; D011471:Prostatic Neoplasms / Q000150:complications*; D015398:Signal Transduction / Q000502:physiology*; D051785:Smad Proteins / Q000502:physiology*
chemical_list: D050659:Core Binding Factor Alpha 1 Subunit; C493709:RUNX2 protein, human; D051785:Smad Proteins; D053495:Osteopontin; D016178:Granulocyte-Macrophage Colony-Stimulating Factor
keywords: Runx2; intratibial tumors; metastatic bone disease; osteoblastic/osteolytic disease; prostate cancer