Inhibition of mTORC1 leads to MAPK pathway activation through a PI3K-dependent feedback loop in human cancer

Carracedo, Arkaitz; Ma, Li; Teruya‐Feldstein, Julie; Rojo, Federico; Salmena, Leonardo; Alimonti, Andrea; Egia, Ainara; Sasaki, Atsuo T.; Thomas, George; Kozma, Sara C.; Papa, Antonella; Nardella, Caterina; Cantley, Lewis C.; Baselga, J.; Pandolfi, Pier Paolo

doi:10.1172/jci34739

Cited by 960 publications

(1,187 citation statements)

References 45 publications

(49 reference statements)

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“…and 4E-BP1, as well as on different compensatory mechanisms which link PI3K/mTOR and MAPK signaling (18,20). Our results demonstrate that prodiginines target mTOR pathway.…”

Section: Discussionmentioning

confidence: 60%

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Identification of dual mTORC1 and mTORC2 inhibitors in melanoma cells: Prodigiosin vs. obatoclax

Espona-Fiedler

Soto‐Cerrato

Hosseini

et al. 2012

Biochemical Pharmacology

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The PI3K/AKT/mTOR signaling pathway regulates cell proliferation, survival and angiogenesis. The mammalian target of rapamycin (mTOR) is a protein kinase ubiquitously expressed within cells that regulates cell growth and survival by integrating nutrient and hormonal signals. mTOR exists in two complexes, mTORC1 and mTORC2. Hyperactivation of the mTOR protein has been linked to development of cancer, raising mTOR as an attractive target for cancer therapy. Prodigiosin (PG) and Obatoclax (OBX), two members of the prodiginines family, are small molecules with anticancer properties which are currently under clinical trials. In the present paper, we demonstrate that mTOR is a molecular target of both prodiginines in melanoma, a highly drug-resistant cancer model. The inhibition of mTORC1 and mTORC2 complexes by PG or OBX resulted in a loss of AKT phosphorylation at S473, preventing its full activation, with no significant effect on T308. The strongest activity inhibition (89%) was induced by PG on mTORC2. Binding assays using Surface Plasmon Resonance (SPR) provide kinetic and affinity data of the interaction of these small molecules with mTOR. In addition, in silico modelling produced a detailed atomic description of the binding modes. These results provide new data to understand the mechanism of action of these molecules, and provide new structural data that will allow the development of more specific mTOR inhibitors for cancer treatment.3

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“…and 4E-BP1, as well as on different compensatory mechanisms which link PI3K/mTOR and MAPK signaling (18,20). Our results demonstrate that prodiginines target mTOR pathway.…”

Section: Discussionmentioning

confidence: 60%

“…These pathways are critical to melanoma progression and both are deregulated in melanoma, but not in normal cells (19,20). Thus, compounds that counteract these feedback loops are considered in cancer therapy.…”

Section: Introductionmentioning

confidence: 99%

Identification of dual mTORC1 and mTORC2 inhibitors in melanoma cells: Prodigiosin vs. obatoclax

Espona-Fiedler

Soto‐Cerrato

Hosseini

et al. 2012

Biochemical Pharmacology

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“…42,43 Inhibition of mTORC1 has been shown to lead to MAPK pathway activation, which is consistent with the results we observed after polyamine pathway activation. 44 Several gene alterations, such as decreased GSTP1 and Nkx3.1 expression, have been implicated in the malignant transformation of normal prostate epithelium to HGPIN. 45 HGPIN is a precursor of invasive prostate carcinoma, 46,47 but little is known about the genetic events involved in the advancement to invasive disease, 48,49 a sequence of events that remains unclear.…”

Section: Discussionmentioning

confidence: 99%

Ornithine Decarboxylase Is Sufficient for Prostate Tumorigenesis via Androgen Receptor Signaling

Shukla–Dave

Castillo-Martín

Chen

et al. 2016

The American Journal of Pathology

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Increased polyamine synthesis is known to play an important role in prostate cancer. We aimed to explore its functional significance in prostate tumor initiation and its link to androgen receptor (AR) signaling. For this purpose, we generated a new cell line derived from normal epithelial prostate cells (RWPE-1) with overexpression of ornithine decarboxylase (ODC) and used it for in vitro and in vivo experiments. We then comprehensively analyzed the expression of the main metabolic enzymes of the polyamine pathway and spermine abundance in 120 well-characterized cases of human prostate cancer and high-grade prostate intraepithelial neoplasia (HGPIN). Herein, we show that the ODCoverexpressing prostate cells underwent malignant transformation, revealing that ODC is sufficient for de novo tumor initiation in 94% of injected mice. This oncogenic capacity was acquired through alteration of critical signaling networks, including AR, EIF2, and mTOR/MAPK. RNA silencing experiments revealed the link between AR signaling and polyamine metabolism. Human prostate cancers consistently demonstrated up-regulation of the main polyamine enzymes analyzed (ODC, polyamine oxidase, and spermine synthase) and reduction of spermine. This phenotype was also dominant in HGPIN, rendering it a new biomarker of malignant transformation. In summary, we report that ODC plays a key role in prostate tumorigenesis and that the polyamine pathway is altered as early as HGPIN. (Am J Pathol 2016, 186: 3131e3145; http://dx

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“…74 The mTOR/Raptor/mLST8/DEPTOR complex (mTORC1) is sensitive to rapamycin and, importantly, inhibits Akt via a negative feedback loop, which involves, at least in part, p70 S6K . 75 This is due to the negative effects that p70 S6K has on insulin receptor substrate-1 (ref. 75) (see Figure 2).…”

Section: Downstream Targets Of Akt Regulating Mtor Activitymentioning

confidence: 99%

“…Assuming that equilibrium exists between these two complexes, when the mTORC1 complex is formed, it could antagonize the formation of the mTORC2 complex and reduce Akt activity. [73][74][75] Thus, at least in principle, inhibition of the mTORC1 complex could result in Akt hyperactivation. This is one problem associated with therapeutic approaches using rapamycin that blocks some actions of mTORC1, but not all.…”

Section: Downstream Targets Of Akt Regulating Mtor Activitymentioning

confidence: 99%

Targeting the translational apparatus to improve leukemia therapy: roles of the PI3K/PTEN/Akt/mTOR pathway

et al. 2011

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Inhibition of mTORC1 leads to MAPK pathway activation through a PI3K-dependent feedback loop in human cancer

Cited by 960 publications

References 45 publications

Identification of dual mTORC1 and mTORC2 inhibitors in melanoma cells: Prodigiosin vs. obatoclax

Identification of dual mTORC1 and mTORC2 inhibitors in melanoma cells: Prodigiosin vs. obatoclax

Ornithine Decarboxylase Is Sufficient for Prostate Tumorigenesis via Androgen Receptor Signaling

Targeting the translational apparatus to improve leukemia therapy: roles of the PI3K/PTEN/Akt/mTOR pathway

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