The PP242 Mammalian Target of Rapamycin (mTOR) Inhibitor Activates Extracellular Signal-regulated Kinase (ERK) in Multiple Myeloma Cells via a Target of Rapamycin Complex 1 (TORC1)/ Eukaryotic Translation Initiation Factor 4E (eIF-4E)/RAF Pathway and Activation Is a Mechanism of Resistance

Hoang, Bao; Benavides, Angelica; Shi, Yijiang; Yang, Yonghui; Frost, Patrick; Gera, Joseph; Lichtenstein, Alan

doi:10.1074/jbc.m111.304626

Cited by 70 publications

(57 citation statements)

References 28 publications

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“…Metformin, on the other hand, inhibited mTOR without the regulatory feedback effects on AKT and MAPK. An effect of mTORC1/2 inhibition was also detected in multiple myeloma cells, with a RAF-dependent activation of ERK (Hoang et al 2012). This indicates that the regulatory networks connecting the AKT with the S6Ks can be modulated, and with fine-tuned inhibitors the growth stimulation could be restrained.…”

Section: Discussionmentioning

confidence: 75%

S6 kinase signaling: tamoxifen response and prognostic indication in two breast cancer cohorts

Bostner¹,

Karlsson²,

Eding³

et al. 2015

Endocrine-Related Cancer

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Detection of signals in the mammalian target of rapamycin (mTOR) and the estrogen receptor (ER) pathways may be a future clinical tool for the prediction of adjuvant treatment response in primary breast cancer. Using immunohistological staining, we investigated the value of the mTOR targets p70-S6 kinase (S6K) 1 and 2 as biomarkers for tamoxifen benefit in two independent clinical trials comparing adjuvant tamoxifen with no tamoxifen or 5 years versus 2 years of tamoxifen treatment. In addition, the prognostic value of the S6Ks was evaluated. We found that S6K1 correlated with proliferation, HER2 status, and cytoplasmic AKT activity, whereas high protein expression levels of S6K2 and phosphorylated (p) S6K were more common in ER-positive, and low-proliferative tumors with pAKT-s473 localized to the nucelus. Nuclear accumulation of S6K1 was indicative of a reduced tamoxifen effect (hazard ratio (HR): 1.07, 95% CI: 0.53-2.81, PZ0.84), compared with a significant benefit from tamoxifen treatment in patients without tumor S6K1 nuclear accumulation (HR: 0.42, 95% CI: 0.29-0.62, P!0.00001). Also S6K1 and S6K2 activation, indicated by pS6K-t389 expression, was associated with low benefit from tamoxifen (HR: 0.97, 95% CI: 0.50-1.87, PZ0.92). In addition, high protein expression of S6K1, independent of localization, predicted worse prognosis in a multivariate analysis, PZ0.00041 (cytoplasm), PZ0.016 (nucleus). In conclusion, the mTOR-activated kinases S6K1 and S6K2 interfere with proliferation and response to tamoxifen. Monitoring their activity and intracellular localization may provide biomarkers for breast cancer treatment, allowing the identification of a group of patients less likely to benefit from tamoxifen and thus in need of an alternative or additional targeted treatment.

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Section: Discussionmentioning

confidence: 75%

S6 kinase signaling: tamoxifen response and prognostic indication in two breast cancer cohorts

Bostner¹,

Karlsson²,

Eding³

et al. 2015

Endocrine-Related Cancer

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“…Interestingly, phosphorylation of some targets of mTORC1, such as 4EBP, is more strongly inhibited by ATP-based inhibitors than by rapamycin, suggesting that rapamycin does not completely block all targets of mTORC1 (Thoreen et al 2012). The increased inhibition of 4EBP can also be linked to the activation of the RAF-MEK-ERK pathway in myeloma cells (Hoang et al 2012). Although this information is of obvious importance to oncobiologists, the possibility of feedback-mediated changes in other signaling pathways induced by mTOR inhibition must also be heeded by neurobiologists wishing to employ them in experiments that assess the role of mTOR in learning and memory.…”

Section: Pharmacological Inhibitionmentioning

confidence: 99%

“…Directed against the mTOR ATP site, these are potent inhibitors of both mTORC1 and mTORC2. Unfortunately, feedback is still an issue with these inhibitors, as the mTOR inhibitory activity of PP242 has been found to generate apoptotic resistance through the potent activation of the RAF-MEK-ERK signaling pathway (Hoang et al 2012). Interestingly, phosphorylation of some targets of mTORC1, such as 4EBP, is more strongly inhibited by ATP-based inhibitors than by rapamycin, suggesting that rapamycin does not completely block all targets of mTORC1 (Thoreen et al 2012).…”

Section: Pharmacological Inhibitionmentioning

confidence: 99%

A recollection of mTOR signaling in learning and memory

2013

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Mechanistic target of rapamcyin (mTOR) is a central player in cell growth throughout the organism. However, mTOR takes on an additional, more specialized role in the developed neuron, where it regulates the protein synthesis-dependent, plastic changes underlying learning and memory. mTOR is sequestered in two multiprotein complexes (mTORC1 and mTORC2) that have different substrate specificities, thus allowing for distinct functions at synapses. We will examine how learning activates the mTOR complexes, survey the critical effectors of this pathway in the context of synaptic plasticity, and assess whether mTOR plays an instructive or permissive role in generating molecular memory traces.

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“…It blocks the phosphorylation of AKT at Ser 473 and prevents its activation. Reported as a complication of PP242, this compound also mediates ERK activation by a mechanism that remains to be elucidated (Hoang et al, 2012). It appears however that its mode of action differs from the one of rapalogs where ERK activation is mediated by a p70S6K-and PI3K-dependent activation of upstream kinases of the MAPK ERK cascade.…”

Section: Low Mw Inducers Targeting Mtor-dependent Autophagymentioning

confidence: 99%

Pharmacological regulators of autophagy and their link with modulators of lupus disease

Gros

Muller

2014

British J Pharmacology

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Autophagy is a central regulator of cell survival. It displays both anti-and pro-death roles that are decisive in the maintenance of cell homeostasis. Initially described in several eukaryotic cellular models as being induced under nutrient stress favouring survival by energy supply, autophagy was found later to display other decisive physiological roles, especially in the immune system. Thus, it is involved in antigen presentation and lymphocyte differentiation as well as in the balance regulating survival/death and activation of lymphocytes. Autophagy therefore appears to be central in the regulation of inflammation. The observation that autophagy is deregulated in systemic lupus erythematosus is recent. This discovery revives the programme dealing with the design and development of pharmacological autophagy regulators in the therapeutic context of lupus, a debilitating autoimmune disease that affects several million people in the world. A large number of molecules that positively and negatively regulate autophagy have been described, most of them with therapeutic indications in cancer and infection. Only a few, however, are effectively potent activators or inhibitors endowed with experimentally demonstrated selective properties. In this review article, we highlight the most relevant ones and summarize what we know regarding their mechanism of action. We emphasize the link between pharmacological regulators of autophagy and inducers or inhibitors of lupus disease and discuss the fundamental and pharmacological/therapeutic interest of this functional interplay. AbbreviationsCMA, chaperone-mediated autophagy; CQ/HCQ, chloroquine/hydroxychloroquine; HSPA8/HSC70, heat shock cognate protein of 70 kDa; LAP, LC3-associated phagocytosis; LC3, microtubule-associated protein light chain 3; MHC-I/II, MHC class I or MHC class II; mTOR, mammalian target of rapamycin; PRR, pattern recognition receptors; SLE, systemic lupus erythematosus TLR 9 RapamycinThis Table lists the protein targets and ligands in this article which are hyperlinked to corresponding entries in http:// www.guidetopharmacology.org, the common portal for data from the IUPHAR/BPS Guide to PHARMACOLOGY (Pawson et al., 2014) and the Concise Guide to PHARMACOLOGY 2013/14 (Alexander et al., 2013a). Autophagy and its implication in human diseasesAutophagy is a catabolic process related to lysosomal degradation. Opposed to heterophagy, which implies degradation of substrates from outside the cell, autophagy catabolizes the cytoplasmic content. There are three main pathways involved in autophagy. The first one, called microautophagy, involves the direct engulfment of cytosolic material into the lysosome. Its core molecular machinery and regulation as well as its possible implication in human diseases are still poorly understood. In this review, we will focus the first part of our comments on the two other types of autophagy, namely, macroautophagy and chaperone-mediated autophagy (CMA). Historically, the term 'autophagy' was proposed by Christian De Duve in the ...

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The PP242 Mammalian Target of Rapamycin (mTOR) Inhibitor Activates Extracellular Signal-regulated Kinase (ERK) in Multiple Myeloma Cells via a Target of Rapamycin Complex 1 (TORC1)/ Eukaryotic Translation Initiation Factor 4E (eIF-4E)/RAF Pathway and Activation Is a Mechanism of Resistance

Cited by 70 publications

References 28 publications

S6 kinase signaling: tamoxifen response and prognostic indication in two breast cancer cohorts

S6 kinase signaling: tamoxifen response and prognostic indication in two breast cancer cohorts

A recollection of mTOR signaling in learning and memory

Pharmacological regulators of autophagy and their link with modulators of lupus disease

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