Effect of transforming growth factor beta (TGF-β) receptor I kinase inhibitor on prostate cancer bone growth

• Published in: Bone (New York, N.Y.) Vol. 50; no. 3; pp. 695 - 703
• Main Authors: Wan, Xinhai, Li, Zhi-Gang, Yingling, Jonathan M, Yang, Jun, Starbuck, Michael W, Ravoori, Murali K, Kundra, Vikas, Vazquez, Elba, Navone, Nora M
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier 01.03.2012
• Subjects: Animals; Antineoplastic Agents - pharmacology; Biological and medical sciences; Bone and Bones - drug effects; Bone Neoplasms - secondary; Cell Line, Tumor; Cell Proliferation - drug effects; Femur - drug effects; Femur - metabolism; Femur - pathology; Fundamental and applied biological sciences. Psychology; Gynecology. Andrology. Obstetrics; Humans; Male; Male genital diseases; Medical sciences; Mice; Nephrology. Urinary tract diseases; Orthopedics; Osteoblasts - drug effects; Osteoblasts - metabolism; Osteoblasts - pathology; Prostatic Neoplasms - pathology; Protein-Serine-Threonine Kinases - antagonists & inhibitors; Protein-Serine-Threonine Kinases - metabolism; Pyrazoles - pharmacology; Pyrroles - pharmacology; Receptors, Transforming Growth Factor beta - antagonists & inhibitors; Receptors, Transforming Growth Factor beta - metabolism; Transforming Growth Factor beta1 - metabolism; Tumor Cells, Cultured; Tumors; Tumors of the urinary system; Urinary tract. Prostate gland; Vertebrates: anatomy and physiology, studies on body, several organs or systems; Xenograft Model Antitumor Assays; rhTGF-β1; bone volume; PMOs; recombinant human TGF-β1; TGF-β RI; TGF-β receptor type I; primary mouse osteoblasts; transforming growth factor beta 1; Bone metastases; PCa; prostate cancer; BV; TGF-β1; TGF-β; glyceraldehyde-3-phosphate dehydrogenase; GAPDH; TGF-β receptor type I kinase inhibitor; Urinary system disease; Prostate disease; Enzyme; Growth; Transforming growth factor β; Transferases; Diseases of the osteoarticular system; Malignant tumor; Bone metastasis; Kinase; Morphology; Bone; Male genital diseases; Prostate cancer; Cancer
• ISSN: 8756-3282; 1873-2763
• DOI: 10.1016/j.bone.2011.11.022

Abstract Transforming growth factor beta 1 (TGF-β1) has been implicated in the pathogenesis of prostate cancer (PCa) bone metastasis. In this study, we tested the antitumor efficacy of a selective TGF-β receptor I kinase inhibitor, LY2109761, in preclinical models. The effect of LY2109761 on the growth of MDA PCa 2b and PC-3 human PCa cells and primary mouse osteoblasts (PMOs) was assessed in vitro by measuring radiolabeled thymidine incorporation into DNA. In vivo , the right femurs of male SCID mice were injected with PCa cells. We monitored the tumor burden in control- and LY2109761-treated mice with MRI analysis and the PCa-induced bone response with X-ray and micro-CT analyses. Histologic changes in bone were studied by performing bone histomorphometric evaluations. PCa cells and PMOs expressed TGF-β receptor I. TGF-β1 induced pathway activation (as assessed by induced expression of p-Smad2) and inhibited cell growth in PC-3 cells and PMOs but not in MDA PCa 2b cells. LY2109761 had no effect on PCa cells but induced PMO proliferation in vitro . As expected, LY2109761 reversed the TGF-β1-induced pathway activation and growth inhibition in PC-3 cells and PMOs. In vivo , LY2109761 treatment for 6 weeks resulted in increased volume in normal bone and increased osteoblast and osteoclast parameters. In addition, LY2109761 treatment significantly inhibited the growth of MDA PCa 2b and PC-3 in the bone of SCID mice ( p < 0.05); moreover, it resulted in significantly less bone loss and change in osteoclast-associated parameters in the PC-3 tumor-bearing bones than in the untreated mice. In summary, we report for the first time that targeting TGF-β receptors with LY2109761 can control PCa bone growth while increasing the mass of normal bone. This increased bone mass in nontumorous bone may be a desirable side effect of LY2109761 treatment for men with osteopenia or osteoporosis secondary to androgen-ablation therapy, reinforcing the benefit of effectively controlling PCa growth in bone. Thus, targeting TGF-β receptor I is a valuable intervention in men with advanced PCa.