mTOR信号通路及其在头颈肿瘤研究中的进展

哺乳动物雷帕霉素靶蛋白(mammalian target of rapamycin,m TOR)在肿瘤的发生、侵袭、转移,甚至肿瘤的局部复发都起着重要的作用。头颈肿瘤作为全球最常见的癌症死亡原因之一,有多元的逐步恶化的过程。近年来研究表明m TOR信号通路的异常表达是头颈肿瘤最常见的病理改变之一,且m TOR信号通路的多种组成元件与头颈肿瘤患者的预后有明显的相关性,这不仅可为头颈肿瘤的特异性靶向治疗提供依据,而且也可为预测头颈肿瘤患者的预后提供参考。本文就m TOR信号通路及其在头颈肿瘤中的作用做一综述,旨在对m TOR信号通路和头颈肿瘤及其预后的关系有更进一步的认识。     

BMP and mTOR signaling in heterotopic ossification: Does their crosstalk provide therapeutic opportunities?

Heterotopic ossification (HO) refers to the pathological formation of ectopic bone in soft tissues, it occurs following severe trauma or in patients with a rare genetic disorder known as fibrodysplasia ossificans progressiva. The pathological process of HO formation is a two-step mechanism: inflammation and destruction of connective tissues, followed by bone formation. The latter is further subdivided into three stages: fibroproliferation/angiogenesis, chondrogenesis, and osteogenesis. Currently, therapeutic options for HO are limited. New potential therapeutics will most likely arise from a more detailed understanding of the signaling pathways implicated in each stage of ectopic bone formation and molecular targets that may be effective at both the early and late stages of HO. Bone morphogenetic protein (BMP) signaling is believed to play a key role in the overall HO process. Recently, the mammalian target of rapamycin (mTOR) signaling pathway has received attention as a critical pathway for chondrogenesis, osteogenesis, and HO. Inhibition of mTOR signaling has been shown to block trauma-induced and genetic HO. Intriguingly, recent studies have revealed crosstalk between mTOR and BMP signaling. Moreover, mTOR has emerged as a factor involved in the early hypoxic and inflammatory stages of HO. We will summarize the current knowledge of the roles of mTOR and BMP signaling in HO, with a particular focus on the crosstalk between mTOR and BMP signaling. We also discuss the activation of AMP activated protein kinase (AMPK) by the most widely used drug for type 2 diabetes, metformin, which exerts a dual negative regulatory effect on mTOR and BMP signaling, suggesting that metformin is a promising drug treatment for HO. The discovery of an mTOR-BMP signaling network may be a potential molecular mechanism of HO and may represent a novel therapeutic target for the pharmacological control of HO.     

Targeting bone metastatic cancer: Role of the mTOR pathway

One of the great challenges of cancer medicine is to develop effective treatments for bone metastatic cancer. Most patients with advanced solid tumors will develop bone metastasis and will suffer from skeletal related events associated with this disease. Although some therapies are available to manage symptoms derived from bone metastases, an effective treatment has not been developed yet.The mammalian target of rapamycin (mTOR) pathway regulates cell growth and survival. Alterations in mTOR signaling have been associated with pathological malignancies, including bone metastatic cancer. Inhibition of mTOR signaling might therefore be a promising alternative for bone metastatic cancer management. This review summarizes the current knowledge on mTOR pathway signaling in bone tissue and provides an overview on the known effects of mTOR inhibition in bone cancer, both in in vitro and in vivo models.     

Perivascular epitheloid cell tumor (PEComa) mimicking retroperitoneal liposarcoma

PEComas are a collection of generally rare tumors, defined by the World Health Organization as ‘mesenchymal tumors composed of histologically and immunohistochemically distinctive perivascular epitheloid cells’. We describe the case of retroperitoneal PEComa with a liposarcoma-like appearance on cross-sectional imaging, but distinctive immunohistochemistry revealing the correct diagnosis.     

An expanding role for mTOR in cancer

Rapamycin, a valuable drug with diverse clinical applications, inhibits mTOR (mammalian target of rapamycin), which is a protein kinase that controls cell growth by regulating many cellular processes, including protein synthesis and autophagy. The sensitivity of select tumor cells to rapamycin has ignited considerable excitement over its potential as an anti-cancer therapeutic. Recent findings identified a rapamycin-insensitive function of mTOR in regulating a cell-survival pathway that is hyperactive in many cancers, particularly those with elevated PtdIns3K signaling or harboring mutations in the tumor suppressor PTEN (phosphatase and tensin homolog deleted on chromosome 10). These new findings suggest that targeting this function of mTOR might have broader applications in cancer therapy. In this article, we re-evaluate mTOR signaling, suggesting a more central role for mTOR in cancers with defective PtdIns3K-PTEN signaling and conceptually discuss these implications in the context of drug discovery.     

mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery

mTOR/RAFT1/FRAP is the target of the immunosuppressive drug rapamycin and the central component of a nutrient- and hormone-sensitive signaling pathway that regulates cell growth. We report that mTOR forms a stoichiometric complex with raptor, an evolutionarily conserved protein with at least two roles in the mTOR pathway. Raptor has a positive role in nutrient-stimulated signaling to the downstream effector S6K1, maintenance of cell size, and mTOR protein expression. The association of raptor with mTOR also negatively regulates the mTOR kinase activity. Conditions that repress the pathway, such as nutrient deprivation and mitochondrial uncoupling, stabilize the mTOR-raptor association and inhibit mTOR kinase activity. We propose that raptor is a missing component of the mTOR pathway that through its association with mTOR regulates cell size in response to nutrient levels.     

Sclerosing variant of PEComa: report of a case and review of the literature

Tumours of perivascular epithelioid cells (PEComas) are a heterogeneous group of uncommon mesenchymal neoplasms which exhibit a peculiar immunohistochemical co-expression of muscle and melanocytic markers. PEComas occur at various visceral and soft tissue sites, generally with a benign clinical course. Nevertheless, there has been evidence of cases having an unfavourable outcome, thus prompting investigation of pathological criteria for malignancy. A sclerosing variant of PEComa, more frequently encountered in the retroperitoneum of middle-aged women, has been reported. Prognosis has generally been regarded as favourable and complete surgical excision appears to be adequate treatment. To the best of our knowledge, only two cases of sclerosing PEComa displayed high-grade malignant morphology and were associated with adverse outcome. An additional case of retroperitoneal sclerosing PEComa with a two-year follow-up and indolent behaviour is herein described. Light and electron microscopy were performed, along with immunohistochemical analysis. Further studies are needed to clarify the histogenesis and to predict the biological behaviour of this uncommon entity.     

Targeting Glutamatergic Signaling and the PI3 Kinase Pathway to Halt Melanoma Progression

Our group has previously reported that the majority of human melanomas (> 60%) express the metabotropic glutamate receptor 1 (GRM1) and that the glutamate release inhibitor riluzole, a drug currently used to treat amyotrophic lateral sclerosis, can induce apoptosis in GRM1-expressing melanoma cells. Our group previously reported that in vitro riluzole treatment reduces cell growth in three-dimensional (3D) soft agar colony assays by 80% in cells with wildtype phosphoinositide 3-kinase (PI3K) pathway activation. However, melanoma cell lines harboring constitutive activating mutations of the PI3K pathway (PTEN and NRAS mutations) showed only a 35% to 40% decrease in colony formation in soft agar in the presence of riluzole. In this study, we have continued our preclinical studies of riluzole and its effect on melanoma cells alone and in combination with inhibitors of the PI3 kinase pathway: the AKT inhibitor, API-2, and the mammalian target of rapamycin (mTOR) inhibitor, rapamycin. We modeled these combinatorial therapies on various melanoma cell lines in 3D and 2D systems and in vivo. Riluzole combined with mTOR inhibition is more effective at halting melanoma anchorage-independent growth and xenograft tumor progression than either agent alone. PI3K signaling changes associated with this combinatorial treatment shows that 3D (nanoculture) modeling of cell signaling more closely resembles in vivo signaling than monolayer models. Riluzole combined with mTOR inhibition is effective at halting tumor cell progression independent of BRAF mutational status. This makes this combinatorial therapy a potentially viable alternative for metastatic melanoma patients who are BRAF WT and are therefore ineligible for vemurafenib therapy.     

Targeting the mTOR Signaling Network for Alzheimer’s Disease Therapy

The mammalian target of rapamycin (mTOR) is a highly conserved serine/threonine kinase that can sense environmental stimuli such as growth factors, energy state, and nutrients. It is essential for cell growth, proliferation, and metabolism, but dysregulation of mTOR signaling pathway is also associated with a number of human diseases. Encouraging data from experiments have provided sufficient evidence for the relationship between the mTOR signaling pathway and Alzheimer’s disease (AD). Upregulation of mTOR signaling pathway is thought to play an important role in major pathological processes of AD. The mTOR inhibitors such as rapamycin have been proven to ameliorate the AD-like pathology and cognitive deficits effectively in a broad range of animal models. Application of mTOR inhibitors indicates the potential value of reducing mTOR activity as an innovative therapeutic strategy for AD. In this review, we will focus on the recent process in understanding mTOR signaling pathway and the vital involvement of this signaling pathway in the pathology of AD, and discuss the application of mTOR inhibitors as potential therapeutic agents for the treatment of AD.     

Leucine-stimulated mTOR signaling is partly attenuated in skeletal muscle of chronically uremic rats

The branched-chain amino acid leucine stimulates muscle protein synthesis in part by directly activating the mTOR signaling pathway. Furthermore, leucine, if given in conjunction with resistance exercise, enhances the exercise-induced mTOR signaling and protein synthesis. Here we tested whether leucine can activate the mTOR anabolic signaling pathway in uremia and whether it can enhance work overload (WO)-induced signaling through this pathway. Chronic kidney disease (CKD) and control rats were studied after 7 days of surgically induced unilateral plantaris muscle WO and a single leucine or saline load. In the basal state, 4E-BP1 phosphorylation was modestly depressed in non-WO muscle of CKD rats, whereas rpS6 phosphorylation was nearly completely suppressed. After oral leucine mTOR, S6K1 and rpS6 phosphorylation increased similarly in both groups, whereas the phospho-4E-BP1 response was modestly attenuated in CKD. WO alone activated the mTOR signaling pathway in control and CKD rats. In WO CKD, muscle leucine augmented mTOR and 4E-BP1 phosphorylation, but its effect on S6K1 phosphorylation was attenuated. Taken together, this study has established that the chronic uremic state impairs basal signaling through the mTOR anabolic pathway, an abnormality that may contribute to muscle wasting. However, despite this abnormality, leucine can stimulate this signaling pathway in CKD, although its effectiveness is partially attenuated, including in skeletal muscle undergoing sustained WO. Thus, although there is some resistance to leucine in CKD, the data suggest a potential role for leucine-rich supplements in the management of uremic muscle wasting.     

The anti-tumor effects of the combination of microwave hyperthermia and lobaplatin against breast cancer cells in vitro and in vivo

Background: Breast cancer is the main lethal disease among females. The combination of lobaplatin and microwave hyperthermia plays a crucial role in several kinds of cancer in the clinic, but its possible mechanism in breast cancer has remained indistinct.Methods: Mouse models were used to detect breast cancer progression. Cell growth was explored with MTS (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulphonyl)-2H-tetrazolium) and colony formation assays. Cell migration and invasion were investigated with a transwell assay. Cell apoptosis was probed with flow cytometry. The expression of apoptosis-associated proteins was examined with Western blots.Result: Combination treatment decreased breast cancer cell viability, colony formation, cell invasion and metastasis. In addition, the treatment-induced breast cancer cell apoptosis and autophagy, activated the c-Jun N-terminal kinase (JNK) signaling pathway, suppressed the protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling pathway, and down-regulated IAP and Bcl-2 family protein expression.Conclusion: These results indicate that lobaplatin is an effective breast cancer anti-tumor agent. Microwave hyperthermia was a useful adjunctive treatment. Combination treatment was more efficient than any single therapy. The possible mechanism for this effect was mainly associated with activation of the JNK signaling pathway, inactivation of the AKT/mTOR signaling pathway and down-regulation of the Bcl-2 and IAP families.     

Discovery of triazine-benzimidazoles as selective inhibitors of mTOR

mTOR is part of the PI3K/AKT pathway and is a central regulator of cell growth and survival. Since many cancers display mutations linked to the mTOR signaling pathway, mTOR has emerged as an important target for oncology therapy. Herein, we report the discovery of triazine benzimidazole inhibitors that inhibit mTOR kinase activity with up to 200-fold selectivity over the structurally homologous kinase PI3Kα. When tested in a panel of cancer cell lines displaying various mutations, a selective inhibitor from this series inhibited cellular proliferation with a mean IC₅₀ of 0.41 μM. Lead compound 42 demonstrated up to 83% inhibition of mTOR substrate phosphorylation in a murine pharmacodynamic model.     

FAK/mTOR信号通在肿瘤细胞中的调控作用

粘附斑激酶（focal adhesion kinase,FAK）是一种胞质非受体酪氨酸激酶,是整合素信号通路里一个重要的调节因子,在肿瘤细胞中高表达,与细胞迁移、粘附和侵袭有关。mTOR (mammalian target of rapamycin)是非典型性的Ser/Thr激酶,属于PIKK（phosphatidylinositol kinase related kinase）超家族,介导营养信号调控细胞生长、分化及代谢等生理过程。近年的研究发现FAK通过三条途径与mTOR相关联,组成FAK/mTOR信号通路,在肿瘤细胞的增殖、迁移及肿瘤微环境中发挥着重要的调控作用。本文综述了FAK、mTOR和FAK/mTOR信号通路的特点及对肿瘤细胞调控作用的研究概况,为肿瘤治疗提供参考。     

Neuroprotection by dipeptidyl-peptidase-4 inhibitors and glucagon-like peptide-1 analogs via the modulation of AKT-signaling pathway in Alzheimer’s disease

Alzheimer’s disease (AD) is the most common reason for progressive dementia in the elderly. It has been shown that disorders of the mammalian/mechanistic target of rapamycin (mTOR) signaling pathways are related to the AD. On the other hand, diabetes mellitus (DM) is a risk factor for the cognitive dysfunction. The pathogenesis of the neuronal impairment caused by diabetic hyperglycemia is intricate, which contains neuro-inflammation and/or neurodegeneration and dementia. Glucagon-like peptide-1 (GLP1) is interesting as a possible link between metabolism and brain impairment. Modulation of GLP1 activity can influence amyloid-beta peptide aggregation via the phosphoinositide-3 kinase/AKT/mTOR signaling pathway in AD. The GLP1 receptor agonists have been shown to have favorable actions on the brain such as the improvement of neurological deficit. They might also exert a beneficial effect with refining learning and memory on the cognitive impairment induced by diabetes. Recent experimental and clinical evidence indicates that dipeptidyl-peptidase-4 (DPP4) inhibitors, being currently used for DM therapy, may also be effective for AD treatment. The DPP-4 inhibitors have demonstrated neuroprotection and cognitive improvements in animal models. Although further studies for mTOR, GLP1, and DPP4 signaling pathways in humans would be intensively required, they seem to be a promising approach for innovative AD-treatments. We would like to review the characteristics of AD pathogenesis, the key roles of mTOR in AD and the preventive and/ or therapeutic suggestions of directing the mTOR signaling pathway.     

Mammalian target of rapamycin: master regulator of cell growth in the nervous system

The mammalian target of rapamycin (mTOR) is a highly conserved serine/threonine protein kinase that regulates a number of diverse biologic processes important for cell growth and proliferation, including ribosomal biogenesis and protein translation. In this regard, hyperactivation of the mTOR signaling pathway has been demonstrated in numerous human cancers, including a number of inherited cancer syndromes in which individuals have an increased risk of developing benign and malignant tumors. Three of these inherited cancer syndromes (Lhermitte-Duclos disease, neurofibromatosis type 1, and tuberous sclerosis complex) are characterized by significant central nervous system dysfunction and brain tumor formation. Each of these disorders is caused by a genetic mutation that disrupts the expression of proteins which negatively regulate mTOR signaling, indicating that the mTOR signaling pathway is critical for appropriate brain development and function. In this review, we discuss our current understanding of the mTOR signaling pathway and its role in promoting ribosome biogenesis and cell growth. We suggest that studies of this pathway may prove useful in identifying molecular targets for biologically-based therapies of brain tumors associated with these inherited cancer syndromes as well as sporadic central nervous system tumors.     

Neuroprotection by dipeptidyl-peptidase-4 inhibitors and glucagon-like peptide-1 analogs via the modulation of AKT-signaling pathway in Alzheimer’s disease

Alzheimer’s disease (AD) is the most common reason for progressive dementia in the elderly. It has been shown that disorders of the mammalian/mechanistic target of rapamycin (mTOR) signaling pathways are related to the AD. On the other hand, diabetes mellitus (DM) is a risk factor for the cognitive dysfunction. The pathogenesis of the neuronal impairment caused by diabetic hyperglycemia is intricate, which contains neuro-inflammation and/or neurodegeneration and dementia. Glucagon-like peptide-1 (GLP1) is interesting as a possible link between metabolism and brain impairment. Modulation of GLP1 activity can influence amyloid-beta peptide aggregation via the phosphoinositide-3 kinase/AKT/mTOR signaling pathway in AD. The GLP1 receptor agonists have been shown to have favorable actions on the brain such as the improvement of neurological deficit. They might also exert a beneficial effect with refining learning and memory on the cognitive impairment induced by diabetes. Recent experimental and clinical evidence indicates that dipeptidyl-peptidase-4 (DPP4) inhibitors, being currently used for DM therapy, may also be effective for AD treatment. The DPP-4 inhibitors have demonstrated neuroprotection and cognitive improvements in animal models. Although further studies for mTOR, GLP1, and DPP4 signaling pathways in humans would be intensively required, they seem to be a promising approach for innovative AD-treatments. We would like to review the characteristics of AD pathogenesis, the key roles of mTOR in AD and the preventive and/ or therapeutic suggestions of directing the mTOR signaling pathway.     

Deconstructing feedback-signaling networks to improve anticancer therapy with mTORC1 inhibitors

Targeting mTOR complex 1 (mTORC1), which regulates general protein translation, represents one of the most attractive approaches to treating cancer, since up-regulation of this pathway is a common hallmark in many tumors. Nevertheless, the use of rapamycin and its analogs in the clinic has revealed that mTORC1 pathway is embedded in a network of signaling cross-talks and feedbacks which might reduce its effectiveness in cancer. We have recently described a novel signaling feedback stemming from mTORC1 inhibition, which leads to the activation of ERK-MAPK (MAPK) pathway. The observation that MAPK is activated by rapamycin and its analogs in vitro, in mouse models, and cancer patient biopsies sets the rationale for the combined use of MAPK and mTORC1 inhibitors in cancer therapy. In this extra-view, we integrate our findings into the mTORC1 signaling network and discuss its relevance for the design of combinatorial therapies with mTORC1 inhibitors.     

Regulation of cell death and epileptogenesis by the mammalian target of rapamycin (mTOR): A double-edged sword?

Identification of cell signaling mechanisms mediating seizure-related neuronal death and epileptogenesis is important for developing more effective therapies for epilepsy. The mammalian target of rapamycin (mTOR) pathway has recently been implicated in regulating neuronal death and epileptogenesis in rodent models of epilepsy. In particular, kainate-induced status epilepticus causes abnormal activation of the mTOR pathway, and the mTOR inhibitor, rapamycin, can decrease the development of neuronal death and chronic seizures in the kainate model. Here, we discuss the significance of these findings and extend them further by identifying upstream signaling pathways through which kainate status epilepticus activates the mTOR pathway and by demonstrating limited situations where rapamycin may paradoxically increase mTOR activation and worsen neuronal death in the kainate model. Thus, the regulation of seizure-induced neuronal death and epileptogenesis by mTOR is complex and may have dual, opposing effects depending on the physiological and pathological context. Overall, these findings have important implications for designing potential neuroprotective and antiepileptogenic therapies that modulate the mTOR pathway.     

G0S2 represses PI3K/mTOR signaling and increases sensitivity to PI3K/mTOR pathway inhibitors in breast cancer

G0/G1 switch gene 2 (G0S2) is a direct retinoic acid target implicated in cancer biology and therapy based on frequent methylation-mediated silencing in diverse solid tumors. We recently reported that low G0S2 expression in breast cancer, particularly estrogen receptor-positive (ER+) breast cancer, correlates with increased rates of recurrence, indicating that G0S2 plays a role in breast cancer progression. However, the function(s) and mechanism(s) of G0S2 tumor suppression remain unclear. In order to determine potential mechanisms of G0S2 anti-oncogenic activity, we performed genome-wide expression analysis that revealed an enrichment of gene signatures related to PI3K/mTOR pathway activation in G0S2 null cells as compared to G0S2 wild-type cells. G0S2 null cells also exhibited a dramatic decreased sensitivity to PI3K/mTOR pathway inhibitors. Conversely, restoring G0S2 expression in human ER+ breast cancer cells decreased basal mTOR signaling and sensitized the cells to pharmacologic mTOR pathway inhibitors. Notably, we provide evidence here that the increase in recurrence seen with low G0S2 expression is especially prominent in patients who have undergone antiestrogen therapy. Further, ER+ breast cancer cells with restored G0S2 expression had a relative increased sensitivity to tamoxifen. These findings reveal that in breast cancer G0S2 functions as a tumor suppressor in part by repressing PI3K/mTOR activity, and that G0S2 enhances therapeutic responses to PI3K/mTOR inhibitors. Recent studies implicate hyperactivation of PI3K/mTOR signaling as promoting resistance to antiestrogen therapies in ER+ breast cancer. Our data establishes G0S2 as opposing this form of antiestrogen resistance. This promotes further investigation of the role of G0S2 as an antineoplastic breast cancer target and a biomarker for recurrence and therapy response.