Mechanical tibial loading remotely suppresses brain tumors by dopamine-mediated downregulation of CCN4

Yao Shan Fan ,Harikrishna Nakshatri,Tomohiko Sano,Jing Liu,Mangilal Agarwal,Shengzhi Liu,Di Wu,Amanda P Siegel,Fangjia Li,Kexin Li,Bai‐Yan Li ,Mark Woollam ,Kazumasa Minami,Motoki Egi,Akihiro Sudo,Rongrong Zha,Takashi Horiuchi,Xinyu Zhao,Xun Sun,Hiroki Yokota

doi: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.

Highlights

Mechanical loading is therapeutically important, in bone homeostasis
While electrostimulation has been shown to elevate dopamine levels in the midbrain,[19] we examined whether loading to the tibia upregulates tyrosine hydroxylase (TH) via Erk signaling and promotes dopamine synthesis in the ventral tegmental area (VTA), which includes abundant dopaminergic neurons.[20]
In response to mechanical loading (5 N at 2 Hz for 5 min) to the left Dopamine receptor D1 mediated tumor suppression by loadingand right tibiae, we observed that TH, a rate-limiting enzyme for driven dopamine dopamine synthesis, was elevated in the VTA in the brain of BALB/c There are two types of dopamine receptors, types D1 and D2, mice 1 h after loading (Fig. 1a, b)

Summary

1234567890();,: INTRODUCTION

Mechanical loading is therapeutically important, in bone homeostasis. Loading to the tibia, for instance, activates canonical Wnt signaling and strengthens the tibia weight-bearing capacity.[1]. The mechanism of remote mechanotransduction from suppressing agent by reducing MTT-assessed cellular viability, the bone to the brain and the role of Lrp5-mediated Wnt signaling, which is required for loading-driven bone gain, need to be elucidated.[21,22] Lrp[5] in cancer cells promotes tumor. Response to the loading-driven elevation of dopamine, we Employing a mouse model of breast-cancer-associated brain evaluated the expression of Lrp[5] and downstream effector genes tumors, we examined the potential therapeutic efficacy of tibial in tumor cells, including tumor-promoting cytokines and oncogenic genes such as Src, Snail, MMP9, Runx[2], and TGFβ.

RESULTS

DISCUSSION

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