Investigation of Novel Regulation of N-myristoyltransferase by Mammalian Target of Rapamycin in Breast Cancer Cells

Jacquier, Marine; Kuriakose, Shiby; Bhardwaj, Apurva; Zhang, Yang; Shrivastav, Anuraag; Portet, Stéphanie; Shrivastav, Shailly Varma

doi:10.1038/s41598-018-30447-0

Cited by 11 publications

(10 citation statements)

References 56 publications

(48 reference statements)

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“…It also indicates that mTORC1 is a novel effector of NMT1 in cancer cells. This is in agreement with the finding that mTOR inhibition increases NMT1 expression in breast cancer cells 47 , possibly due to a compensatory mechanism to increase LAMTOR1 myristoylation and restore mTORC1 activity in cells treated with mTOR inhibitors. We observed that NMTi treatment not only prevented LAMTOR1 localization, but also decreased total LAMTOR1 protein levels.…”

Section: Discussionsupporting

confidence: 92%

N-myristoyltransferase-1 is necessary for lysosomal degradation and mTORC1 activation in cancer cells

Chen

Navarrete

Wang

et al. 2020

Sci Rep

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N-myristoyltransferase-1 (NMT1) catalyzes protein myristoylation, a lipid modification that is elevated in cancer cells. NMT1 sustains proliferation and/or survival of cancer cells through mechanisms that are not completely understood. We used genetic and pharmacological inhibition of NMT1 to further dissect the role of this enzyme in cancer, and found an unexpected essential role for NMT1 at promoting lysosomal metabolic functions. Lysosomes mediate enzymatic degradation of vesicle cargo, and also serve as functional platforms for mTORC1 activation. We show that NMT1 is required for both lysosomal functions in cancer cells. Inhibition of NMT1 impaired lysosomal degradation leading to autophagy flux blockade, and simultaneously caused the dissociation of mTOR from the surface of lysosomes leading to decreased mTORC1 activation. The regulation of lysosomal metabolic functions by NMT1 was largely mediated through the lysosomal adaptor LAMTOR1. Accordingly, genetic targeting of LAMTOR1 recapitulated most of the lysosomal defects of targeting NMT1, including defective lysosomal degradation. Pharmacological inhibition of NMT1 reduced tumor growth, and tumors from treated animals had increased apoptosis and displayed markers of lysosomal dysfunction. Our findings suggest that compounds targeting NMT1 may have therapeutic benefit in cancer by preventing mTORC1 activation and simultaneously blocking lysosomal degradation, leading to cancer cell death. Myristoylation consists of the transfer of the fatty acid myristic acid to proteins 1 , and is catalyzed in vertebrates by two isoenzymes called N-myristoyltransferases (NMTs): NMT1 2 and NMT2 3. Myristoylation increases the affinity of proteins for plasma and internal cell membranes and modulates protein activity by a number of mechanisms 1,4. NMT1 is essential for early embryonic development 5 , and deletion of both isoenzymes impairs T cell development and activation in mice 6. NMT1 expression is increased in cancer 7 , associates with poor patient outcome 8 , and has been considered as a target for therapeutic intervention 9. Accordingly, NMT1 activity promotes proliferation and survival of ovarian and colon cancer cells 10 , facilitates cancer cells survival through AMPKβ-dependent regulation of mitophagy 8 , promotes Src-dependent cell cycle progression in prostate cancer 11 , and regulates proteostasis 12,13 .

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Section: Discussionsupporting

confidence: 92%

N-myristoyltransferase-1 is necessary for lysosomal degradation and mTORC1 activation in cancer cells

Chen

Navarrete

Wang

et al. 2020

Sci Rep

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“…Such models can be analysed using the tools presented here. Results obtained will form a basis for model comparison, which provides a powerful tool to identify mechanisms that drive dynamics (see for example [19,26,34,33]). With a given set of experimental data, such models can be fitted, for example via a Bayesian approach [4].…”

Section: Conclusion and Discussionmentioning

confidence: 99%

A mathematical analysis of an activator-inhibitor Rho GTPase model

Juma

Dehmelt

Portet

et al. 2022

JCD

Self Cite

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<p style='text-indent:20px;'>Recent experimental observations reveal that local cellular contraction pulses emerge via a combination of fast positive and slow negative feedbacks based on a signal network composed of Rho, GEF and Myosin interactions [<xref ref-type="bibr" rid="b22">22</xref>]. As an examplary, we propose to study a plausible, hypothetical temporal model that mirrors general principles of fast positive and slow negative feedback, a hallmark for activator-inhibitor models. The methodology involves (ⅰ) a qualitative analysis to unravel system switching between different states (stable, excitable, oscillatory and bistable) through model parameter variations; (ⅱ) a numerical bifurcation analysis using the positive feedback mediator concentration as a bifurcation parameter, (ⅲ) a sensitivity analysis to quantify the effect of parameter uncertainty on the model output for different dynamic regimes of the model system; and (ⅳ) numerical simulations of the model system for model predictions. Our methodological approach supports the role of mathematical and computational models in unravelling mechanisms for molecular and developmental processes and provides tools for analysis of temporal models of this nature.</p>

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“…The overexpression of p16 INK4A ultimately engages RB to suppress growth and cell cycle progression and promotes oncogene-induced senescence [14]. The dysregulation of INK4 has been associated with poor response to endocrine therapy [15]. Moreover, it has been observed that the loss of the tumor suppressor gene Cyclin Dependent Kinase Inhibitor 2A ( CDKN2A ), which encodes for p16 INK4A, is one of the most common abnormalities in BC, causing uncontrolled activation of CDK4/6, which leads to abnormal cell proliferation [15,16].…”

Section: Biological Mechanisms Behind Endocrine Resistancementioning

confidence: 99%

“…The dysregulation of INK4 has been associated with poor response to endocrine therapy [15]. Moreover, it has been observed that the loss of the tumor suppressor gene Cyclin Dependent Kinase Inhibitor 2A ( CDKN2A ), which encodes for p16 INK4A, is one of the most common abnormalities in BC, causing uncontrolled activation of CDK4/6, which leads to abnormal cell proliferation [15,16]. Everolimus, an mTOR inhibitor, was, in combination with AI, the first target drug developed with the aim of overcoming endocrine resistance [17].…”

Section: Biological Mechanisms Behind Endocrine Resistancementioning

confidence: 99%

The PI3K/AKT/mTOR and CDK4/6 Pathways in Endocrine Resistant HR+/HER2− Metastatic Breast Cancer: Biological Mechanisms and New Treatments

Presti

Quaquarini

2019

Cancers

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Endocrine-based treatments are the normal standard-of-care in women with hormone receptor-positive/Human Epidermal growth factor Receptor 2-negative metastatic breast cancer. Despite the well-known efficacy of these drugs as first-line therapies, about 50% of women develop endocrine resistance and disease progression. The treatment of these patients has represented one of the most important research fields in the last few years, with several multicenter phase II/III trials published or still ongoing. Novel therapies, such as cyclin-dependent kinase (CDK)4/6 and phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) inhibitors, have significantly changed the prognosis of patients progressing to a previous endocrine treatment, allowing a great benefit in terms of progression-free survival and, in some cases, of overall survival. However, identifying response predictors is essential for the rational use of these drugs to avoid unnecessary toxicity and costs, and to ensure the optimal therapeutic sequence is used. In this review, we analyze the PI3K/AKT/mTOR and CDK4/6 pathways and their roles in endocrine resistant metastatic breast cancer. We then focus on the new treatments developed and the roles of these drugs in overcoming endocrine resistance, describing the latest clinical trials that led to the approval of the drugs in clinical practice.

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Investigation of Novel Regulation of N-myristoyltransferase by Mammalian Target of Rapamycin in Breast Cancer Cells

Cited by 11 publications

References 56 publications

N-myristoyltransferase-1 is necessary for lysosomal degradation and mTORC1 activation in cancer cells

N-myristoyltransferase-1 is necessary for lysosomal degradation and mTORC1 activation in cancer cells

A mathematical analysis of an activator-inhibitor Rho GTPase model

The PI3K/AKT/mTOR and CDK4/6 Pathways in Endocrine Resistant HR+/HER2− Metastatic Breast Cancer: Biological Mechanisms and New Treatments

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