Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P42345 (mTOR)
 26,049 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Rapamycins are immunosuppressant and anti-cancer drugs that inhibit the kinase mTOR. Clinically, they often cause bone pain, bone necrosis, and high bone turnover, yet the mechanisms are unclear. Here we show that mTORC1 activity is high in osteoclast precursors but downregulated upon RANKL treatment. Loss-of-function genetic models reveal that while early Raptor deletion in hematopoietic stem cells blunts osteoclastogenesis due to compromised proliferation/survival, late Raptor deletion in osteoclast precursors instead augments osteoclastogenesis. Gain-of-function genetic models by TSC1 deletion in HSCs or osteoclast precursors cause constitutive mTORC1 activation, impairing osteoclastogenesis. Pharmacologically, rapamycin treatment at low but clinically relevant doses exacerbates osteoclast differentiation and bone resorption, leading to bone loss. Mechanistically, RANKL inactivates mTORC1 via calcineurin-mediated mTORC1 dephosphorylation, consequently activating NFATc1 by reducing mTORC1-mediated NFATc1 phosphorylation. These findings uncover biphasic roles of mTORC1 in osteoclastogenesis, dosage-dependent effects of rapamycin on bone, and a previously unrecognized calcineurin-mTORC1-NFATc1 phosphorylation-regulatory signaling cascade.
 ...
PMID:mTORC1 impedes osteoclast differentiation via calcineurin and NFATc1. 3027 15

Bone metastasis causes bone pain and pathological bone fracture in breast cancer patients with a serious complication. Previous studies have demonstrated that a novel phosphatidyl inositol 3-kinase (PI3K)-mTOR inhibitor PKI-402 suppressed the growth of breast cancer cells. However, the role of PKI-402 involved in osteolysis induced by breast cancer remains unclear. In this study, we showed that treatment of PKI-402 led to significant decreases in RANKL-induced osteoclastogenesis and osteoclast-specific gene expression in mouse bone marrow-derived macrophages and reduced proliferation, migration and invasion of MDA-MB-231 breast cancer cells by blocking the PI3K-AKT-mTOR signaling pathway. Importantly, as evidenced by the observation that the administration of PKI-402 inhibited MDA-MB-231-induced osteolysis in vivo, PKI-402 exerted an inhibitory effect on osteoclast formation and bone resorption, critical for cancer cells-induced bone destruction. These results strongly suggest that PKI-402 might have a therapeutic potential to inhibit breast cancer induced osteolysis.
 ...
PMID:Phosphatidyl inositol 3-kinase (PI3K)-mTOR inhibitor PKI-402 inhibits breast cancer induced osteolysis. 3054 Sep 26

Crucial to the development and maintenance of pain sensations is neurotrophin receptor p75 (p75NTR), the low affinity receptor of brain-derived neurotrophic factor (BDNF). This receptor is widespread among dorsal root ganglion (DRG) neurons and the spinal cord. Few reports have demonstrated the specific role of p75NTR in the development of cancer-induced bone pain (CIBP). Therefore the present study examined whether p75NTR contributed to CIBP by upregulating mammalian target of rapamycin (mTOR) signaling. A CIBP rat model was induced and reverse transcription-quantitative polymerase chain reaction was employed to determine p75NTR and mTOR mRNA expression. Immunofluorescence analysis was performed to determine the coexpression of p75NTR and mTOR in DRG neurons, as well as the spinal cord. Von Frey filaments were used to measure the 50% likelihood of paw withdrawal thresholds (PWTs). Spontaneous pain was assessed by ambulatory score. The results demonstrated that compared with the control group, mTOR activation in primary cultured DRG neurons was significantly increased. In addition, mTOR and p75NTR expression was significantly enhanced in the BDNF-treated primary DRG in the BDNF group. In vivo experiments determined that mTOR and p75NTR levels were increased in the CIBP rats compared with the sham group. PWT, in response to mechanical stimulation, was significantly lower compared with that in sham rats and the ambulatory score was significantly higher than that in sham rats. Finally, intrathecal injection of a p75NTR-targeting small interfering RNA significantly decreased mTOR and p75NTR expression levels in DRG neurons and the spinal cord of CIBP rats, as well as partially reversing the decline in PWTs and the increase in ambulatory score. In conclusion, the present study determined that the activation of BDNF/p75NTR/mTOR signaling may participate in nociceptive transmission in CIBP, suggesting a novel mechanism and potential therapeutic target for CIBP treatment and management.
 ...
PMID:Low-affinity neurotrophin receptor p75 of brain-derived neurotrophic factor contributes to cancer-induced bone pain by upregulating mTOR signaling. 3225 64