Mammalian target of rapamycin inhibitors activate the AKT kinase in multiple myeloma cells by up-regulating the insulin-like growth factor receptor/insulin receptor substrate-1/phosphatidylinositol 3-kinase cascade

Shi, Yijiang; Yan, Haiying; Frost, Patrick; Gera, Joseph; Lichtenstein, Alan

doi:10.1158/1535-7163.mct-05-0068

Cited by 339 publications

(278 citation statements)

References 24 publications

(25 reference statements)

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“…4A), suggesting that rapamycin had released mTOR-induced feedback inhibition on IGF1R signaling. Similar enhancement of Akt phosphorylation has been observed following rapamycin treatment in myeloblasts, myeloma, prostate and breast cancer cells in vitro, and in RCC biopsies following clinical mTOR inhibitor treatment (44)(45)(46), suggesting that this phenomenon is clinically relevant.…”

Section: Rapamycin-induced Akt Activation Is Abrogated By Igf1r Deplesupporting

confidence: 63%

Validation of the type 1 insulin-like growth factor receptor as a therapeutic target in renal cancer

Yuen

Akkaya

Wang

et al. 2009

Molecular Cancer Therapeutics

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Purpose: Expression of the type 1 insulin-like growth factor receptor (IGF1R) confers adverse prognosis in clear cell renal cell cancer (CC-RCC). We recently showed that IGF1R expression is inhibited by the von Hippel-Lindau (VHL) tumor suppressor, and the IGF1R is up-regulated in CC-RCC, in which VHL is frequently inactivated. We tested the hypothesis that IGF1R up-regulation mediates resistance to cancer therapeutics, evaluating the effects of IGF1R depletion on sensitivity to cytotoxic drugs, which are ineffective in RCC, and the mammalian target of rapamycin (mTOR) inhibitor rapamycin, analogues of which have clinical activity in this tumor. Experimental Design: This study used CC-RCC cells harboring mutant VHL, and isogenic cells expressing functional VHL. Cells were transfected with nonsilencing control small interfering RNA (siRNA), or with one of two different IGF1R siRNAs. The more potent siRNA was modified by 2′-O-methyl derivatization for in vivo administration. Results: CC-RCC cells expressing mutant VHL and higher IGF1R were more chemoresistant than cells expressing functional VHL. IGF1R depletion induced apoptosis, blocked cell survival, and sensitized to 5-fluorouracil and etoposide. These effects were significantly greater in CC-RCC cells expressing mutant VHL, supporting the hypothesis that IGF1R up-regulation makes a major contribution to the chemoresistance associated with VHL loss.

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Section: Rapamycin-induced Akt Activation Is Abrogated By Igf1r Deplesupporting

confidence: 63%

Validation of the type 1 insulin-like growth factor receptor as a therapeutic target in renal cancer

Yuen

Akkaya

Wang

et al. 2009

Molecular Cancer Therapeutics

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“…On the other hand, recent investigations showed that mTOR inhibition activates the upstream signaling such as Akt (Shi et al, 2005;O'Reilly et al, 2006). Therefore, we determined whether rapamycin or mTOR siRNA stimulates the phosphorylation of Akt in malignant glioma cells.…”

Section: Enhancement Of the Rapamycin-induced Antitumor Effect On Malmentioning

confidence: 93%

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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“…Conversely, S6K1 −/− cells are hypersensitive to insulin activation of PI3K signaling [26,27]. Treatment of some cancer cells with rapamycin upregulates Akt, which can enhance survival under conditions that usually induce apoptosis [23,[28][29][30]. As a result, there is concern that reactivation of Akt in tumors following rapamycin treatment could lead to resistance to other chemotherapeutic agents.…”

Section: Mtor Signal Transduction and Cellular Functionsmentioning

confidence: 99%

Rapamycin and mTOR kinase inhibitors

2008

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Mammalian target of rapamycin (mTOR) is a protein kinase that controls cell growth, proliferation, and survival. mTOR signaling is often upregulated in cancer and there is great interest in developing drugs that target this enzyme. Rapamycin and its analogs bind to a domain separate from the catalytic site to block a subset of mTOR functions. These drugs are extremely selective for mTOR and are already in clinical use for treating cancers, but they could potentially activate an mTOR-dependent survival pathway that could lead to treatment failure. By contrast, small molecules that compete with ATP in the catalytic site would inhibit all of the kinase-dependent functions of mTOR without activating the survival pathway. Several non-selective mTOR kinase inhibitors have been described and here we review their chemical and cellular properties. Further development of selective mTOR kinase inhibitors holds the promise of yielding potent anticancer drugs with a novel mechanism of action.

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Mammalian target of rapamycin inhibitors activate the AKT kinase in multiple myeloma cells by up-regulating the insulin-like growth factor receptor/insulin receptor substrate-1/phosphatidylinositol 3-kinase cascade

Cited by 339 publications

References 24 publications

Validation of the type 1 insulin-like growth factor receptor as a therapeutic target in renal cancer

Validation of the type 1 insulin-like growth factor receptor as a therapeutic target in renal cancer

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

Rapamycin and mTOR kinase inhibitors

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