Mammalian Target of Rapamycin (mTOR): Pro- and Anti-Apoptotic

Castedo, Maria; Ferri, Karine F.; Kroemer, Guido

doi:10.1038/sj.cdd.4400978

Cited by 215 publications

(154 citation statements)

References 24 publications

(12 reference statements)

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“…mTOR acts as a molecular link between apoptosis and autophagy (Castedo et al, 2002). mTOR inhibitors induce apoptosis in some types of tumor cells (Hosoi et al, 1999;Nepomuceno et al, 2003;Majumder et al, 2004;Avellino et al, 2005), whereas they trigger autophagy in other settings (Noda and Ohsumi, 1998;Gutierrez et al, 2004;Kanazawa et al, 2004;Ravikumar et al, 2004) as well as in malignant glioma cells as shown in this study and our previous investigation (Takeuchi et al, 2005).…”

Section: Discussionsupporting

confidence: 77%

Silencing mammalian target of rapamycin signaling by small interfering RNA enhances rapamycin-induced autophagy in malignant glioma cells

et al. 2006

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The mammalian target of rapamycin (mTOR) plays a central role in regulating the proliferation of malignant glioma cells, and mTOR-specific inhibitors such as rapamycin analogs are considered as promising therapy for malignant gliomas. However, the efficacy of mTOR inhibitors alone in the treatment of patients with malignant gliomas is only modest, potentially because these agents rather than acting as mTOR kinase inhibitors instead interfere with the function of only mTOR/raptor (regulatory-associated protein of mTOR) complex and thus do not perturb all mTOR functions. The purpose of this study was to determine whether global inhibition of the mTOR molecule enhances the antitumor effect of rapamycin on malignant glioma cells. We showed that rapamycin induced autophagy and that inhibition of autophagy by small interfering RNA (siRNA) directed against autophagyrelated gene Beclin 1 attenuated the cytotoxicity of rapamycin in rapamycin-sensitive tumor cells, indicating that the autophagy was a primary mediator of rapamycin's antitumor effect rather than a protective response. Exogenous expression of an mTOR mutant interfering with its kinase activity markedly enhanced the incidence of rapamycin-induced autophagy. Moreover, silencing of mTOR with siRNA augmented the inhibitory effect of rapamycin on tumor cell viability by stimulating autophagy. Importantly, not only rapamycin-sensitive malignant glioma cells with PTEN mutations but also rapamycin-resistant malignant glioma cells with wild-type PTEN were sensitized to rapamycin by mTOR siRNA. These results indicate that rapamycin-induced autophagy is one of the agent's antitumor effects and that silencing or inhibiting mTOR kinase activity could enhance the effectiveness of rapamycin.

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Section: Discussionsupporting

confidence: 77%

Silencing mammalian target of rapamycin signaling by small interfering RNA enhances rapamycin-induced autophagy in malignant glioma cells

et al. 2006

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“…Consistent with this, PTEN-negative tumors are particularly good targets for mTOR inhibitors [9,10]. mTOR, originally identified as the mammalian target of rapamycin, is a serine/threonine kinase that plays a central role in control of translation and also regulates anti-apoptotic signals (reviewed in Castedo et al [11]). The potential clinical utility of inhibition of the mTOR pathway in CaP is supported by published reports of inhibition of CaP growth by rapamycin and its derivatives [12][13][14][15][16][17].…”

Section: Introductionmentioning

confidence: 82%

RAD001 (Everolimus) inhibits growth of prostate cancer in the bone and the inhibitory effects are increased by combination with docetaxel and zoledronic acid

et al. 2008

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“…In addition, cell survival is heavily regulated by the mTOR pathway. 85 Dysregulated apoptosis in immune cells 86 and neuronal cells 87 has been described in ASD, which suggests that mechanisms controlling cell survival are altered. PTEN is a major upstream regulator in the mTOR pathway, and mutations in this protein are associated with higher rates of ASD.…”

Section: Deficits In Immune and Neurological Signaling Pathwaysmentioning

confidence: 99%

Immune Dysfunction in Autism: A Pathway to Treatment

2010

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Summary: Autism is a complex and clinically heterogeneous disorder with a spectrum of symptoms. Clinicians, schools, and service agencies worldwide have reported a dramatic increase in the number of children identified with autism. Despite expanding research, the etiology and underlying biological processes of autism remain poorly understood, and the relative contribution from genetic, epigenetic, and environmental factors remains unclear. Although autism affects primarily brain function (especially affect, social functioning, and cognition), it is unknown to what extent other organs and systems are disrupted. Published findings have identified widespread changes in the immune systems of children with autism, at both systemic and cellular levels. Brain specimens from autism subjects exhibit signs of active, ongoing inflammation, as well as alterations in gene pathways associated with immune signaling and immune function. Moreover, many genetic studies have indicated a link between autism and genes that are relevant to both the nervous system and the immune system. Alterations in these pathways can affect function in both systems. Together, these reports suggest that autism may in fact be a systemic disorder with connections to abnormal immune responses. Such immune system dysfunction may represent novel targets for treatment. A better understanding of the involvement of the immune response in autism, and of how early brain development is altered, may have important therapeutic implications.

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Mammalian Target of Rapamycin (mTOR): Pro- and Anti-Apoptotic

Cited by 215 publications

References 24 publications

Silencing mammalian target of rapamycin signaling by small interfering RNA enhances rapamycin-induced autophagy in malignant glioma cells

Silencing mammalian target of rapamycin signaling by small interfering RNA enhances rapamycin-induced autophagy in malignant glioma cells

RAD001 (Everolimus) inhibits growth of prostate cancer in the bone and the inhibitory effects are increased by combination with docetaxel and zoledronic acid

Immune Dysfunction in Autism: A Pathway to Treatment

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