Phosphoproteomic Profiling of Rat's Dorsal Root Ganglia Reveals mTOR as a Potential Target in Bone Cancer Pain and Electro-Acupuncture's Analgesia.

Wen Wang,Jianqiao Fang,Yangqian Cai,Yi Liang,Junying Du,Boyi Liu,Fangbing Shao,Xiaomei Shao,You Zhou,Sisi Wang,Jinggen Liu,Junfan Fang

doi:10.3389/fphar.2021.593043

Abstract

Bone cancer pain (BCP) is a clinical refractory mixed pain involving neuropathic and inflammatory pain, with the underlying mechanisms remaining largely unknown. Electro-acupuncture (EA) can partly alleviate BCP according to previous research. We aim to explore the proteins and major pathways involved in BCP and EA treatment through phosphoproteomic profiling. BCP rat model was built by tibial inoculation of MRMT-1 mammary gland carcinoma cells. Mechanical hyperalgesia determined by paw withdrawal thresholds (PWTs) and bone destruction manifested on the radiographs confirmed the success of modeling, which were attenuated by EA treatment. The differentially expressed phosphorylated proteins (DEPs) co-regulated by BCP modeling and EA treatment in rat dorsal root ganglions (DRGs) were analyzed through PEX100 Protein microarray. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis revealed that DEPs were significantly enriched in mammalian target of rapamycin (mTOR) signaling pathway. The phosphorylations of mTOR at Ser2448 and Thr2446 were increased in BCP and downregulated by EA. In addition, the phosphorylation of S6K and Akt, markers of the mTOR complex, were also increased in BCP and downregulated by EA. Inhibition of mTOR signaling alleviated the PWTs of BCP rats, while the mTOR agonist impaired the analgesic effect of EA. Thus, our study provided a landscape of protein phosphorylation changes in DRGs of EA-treated BCP rats and revealed that mTOR signaling can be potentially targeted to alleviate BCP by EA treatment.

Highlights

Bone cancer pain (BCP) is caused by bone metastasis from tumor and has both pathological features of neuropathic pain and inflammatory pain, which remains clinically challenging
The paw withdraw thresholds (PWTs) of rats were obviously decreased 10 days after BCP operation compared with the control group and kept steadily dropping till postoperative day of 17 (p
The majority of studies focus on specific molecule, but little is known regarding the alterations in the phosphoproteomic profile in dorsal root ganglions (DRGs) of BCP rats, especially in the field of EA analgesia (Largent-Milnes et al, 2008; Gaspari et al, 2017; Deng et al, 2019)

Summary

Introduction

Bone cancer pain (BCP) is caused by bone metastasis from tumor and has both pathological features of neuropathic pain and inflammatory pain, which remains clinically challenging. The incidence of cancer pain in advanced or metastatic cancer patients who received anticancer treatment was reported as 66% (van den Beuken-van Everdingen et al, 2016; Bennett, 2017), of which bone metastases-induced cancer pain was the most common (Meuser et al, 2001). Opioids are the main drugs for cancer pain treatment, and they are strongly recommended by the WHO for moderate and severe cancer pain control under the guidance of the three-step analgesic principle. The adverse effects or the improper use of opioid drugs such as morphine was a matter of concern, which leads to inadequate control of cancer pain (Xia, 2017; Arthur and Reddy, 2019). How to increase the efficiency of cancer pain management and explore a multiplemode therapeutic regimen maintain to be a hot area in pain research

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