Mechanical tibial loading remotely suppresses brain tumors by dopamine-mediated downregulation of CCN4
Open Access
- 24 May 2021
- journal article
- research article
- Published by Springer Science and Business Media LLC in Bone Research
- Vol. 9 (1), 1-10
- https://doi.org/10.1038/s41413-021-00144-2
Abstract
Mechanical loading to the bone is known to be beneficial for bone homeostasis and for suppressing tumor-induced osteolysis in the loaded bone. However, whether loading to a weight-bearing hind limb can inhibit distant tumor growth in the brain is unknown. We examined the possibility of bone-to-brain mechanotransduction using a mouse model of a brain tumor by focusing on the response to Lrp5-mediated Wnt signaling and dopamine in tumor cells. The results revealed that loading the tibia with elevated levels of tyrosine hydroxylase, a rate-limiting enzyme in dopamine synthesis, markedly reduced the progression of the brain tumors. The simultaneous application of fluphenazine (FP), an antipsychotic dopamine modulator, enhanced tumor suppression. Dopamine and FP exerted antitumor effects through the dopamine receptors DRD1 and DRD2, respectively. Notably, dopamine downregulated Lrp5 via DRD1 in tumor cells. A cytokine array analysis revealed that the reduction in CCN4 was critical for loading-driven, dopamine-mediated tumor suppression. The silencing of Lrp5 reduced CCN4, and the administration of CCN4 elevated oncogenic genes such as MMP9, Runx2, and Snail. In summary, this study demonstrates that mechanical loading regulates dopaminergic signaling and remotely suppresses brain tumors by inhibiting the Lrp5-CCN4 axis via DRD1, indicating the possibility of developing an adjuvant bone-mediated loading therapy.Keywords
Funding Information
- U.S. Department of Health & Human Services | NIH | National Cancer Institute (R03 CA238555)
- U.S. Department of Health & Human Services | NIH | National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01 AR052144)
This publication has 43 references indexed in Scilit:
- Current approaches to the treatment of metastatic brain tumoursNature Reviews Clinical Oncology, 2014
- Physical Weight Loading Induces Expression of Tryptophan Hydroxylase 2 in the Brain StemPLOS ONE, 2014
- LRP5 knockdown: effect on prostate cancer invasion growth and skeletal metastasis in vitro and in vivoCancer Medicine, 2013
- WNT signaling in bone homeostasis and disease: from human mutations to treatmentsNature Medicine, 2013
- Mechanotransduction in bone tissue: The A214V and G171V mutations in Lrp5 enhance load-induced osteogenesis in a surface-selective mannerBone, 2012
- Internal loads in the human tibia during gaitClinical Biomechanics, 2009
- The Wnt Co-receptor LRP5 Is Essential for Skeletal Mechanotransduction but Not for the Anabolic Bone Response to Parathyroid Hormone TreatmentOnline Journal of Public Health Informatics, 2006
- Transcranial electrostimulation effects on rat opioid and neurotransmitter levelsLife Sciences, 1994
- Central dopaminergic activity influences rats ability to exerciseLife Sciences, 1985
- Long-term human breast carcinoma cell lines of metastatic origin: Preliminary characterizationIn Vitro Cellular & Developmental Biology - Plant, 1978