The physiology and pathophysiology of rapamycin resistance

Gruppuso, Philip A.; Boylan, Joan M.; Sanders, Jennifer

doi:10.4161/cc.10.7.15230

Cited by 28 publications

(23 citation statements)

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“…The results of our studies indicated resistance to the growth inhibitory effect of rapamycin at the level of G1 cell-cycle progression (13) and translation of 5=TOP mRNAs (12,14). We have also had a long-standing interest in the regulation of hepatic gene expression by mTOR (13,19,21). In the present study, we have extended these observations by characterizing the effect of rapamycin on the hepatic transcriptome and translatome in the late gestation fetal rat and in the adult rat.…”

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confidence: 58%

“…A number of years ago, we made the observation that fetal hepatocytes in vivo were resistant to the growth inhibitory effects of rapamycin despite the ability of the drug to potently inhibit mTORC1 signaling (5,32). Further studies indicated that rapamycin induced hepatocyte cell-cycle arrest at the level of cyclin E-dependent kinase activity in rats that underwent partial hepatectomy and that fetal hepatocytes in vivo were resistant to this effect (13). We went on to show that the translation of 5=TOP mRNAs was similarly sensitive to rapamycin in adult rats that underwent partial hepatectomy but resistant in the late-gestation fetus (14).…”

Section: Discussionmentioning

confidence: 99%

“…Fetal liver was indeed resistant to the inhibitory effects of rapamycin on a defined subset of RNA species with complex 5= untranslated regions. Aside from our observations on late-gestation liver development, observations on rapamycin resistance have been confined to cancer pathophysiology (13). Determination of the mecha- The current data sets were analyzed in Gene Set Enrichment Analysis using the gene sets generated by Thoreen et al (39).…”

Section: R32mentioning

confidence: 99%

“…We went on to examine the hepatic translation control apparatus in the late gestation fetus (14). The results of our studies indicated resistance to the growth inhibitory effect of rapamycin at the level of G1 cell-cycle progression (13) and translation of 5=TOP mRNAs (12,14). We have also had a long-standing interest in the regulation of hepatic gene expression by mTOR (13,19,21).…”

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confidence: 99%

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Profiling of the fetal and adult rat liver transcriptome and translatome reveals discordant regulation by the mechanistic target of rapamycin (mTOR)

Boylan

Sanders

Neretti

et al. 2015

American Journal of Physiology-Regulatory, Integrative and Comp

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of the fetal and adult rat liver transcriptome and translatome reveals discordant regulation by the mechanistic target of rapamycin (mTOR). Am J Physiol Regul Integr Comp Physiol 309: R22-R35, 2015. First published April 29, 2015 doi:10.1152/ajpregu.00114.2015.-The mechanistic target of rapamycin (mTOR) integrates growth factor signaling, nutrient abundance, cell growth, and proliferation. On the basis of our interest in somatic growth in the late gestation fetus, we characterized the role of mTOR in the regulation of hepatic gene expression and translation initiation in fetal and adult rats. Our strategy was to manipulate mTOR signaling in vivo and then characterize the transcriptome and translating mRNA in liver tissue. In adult rats, we used the nonproliferative growth model of refeeding after a period of fasting and the proliferative model of liver regeneration following partial hepatectomy. We also studied livers from preterm fetal rats (embryonic day 19) in which fetal hepatocytes are asynchronously proliferating. All three models employed rapamycin to inhibit mTOR signaling. Analysis of the transcriptome in fasted-refed animals showed rapamycin-mediated induction of genes associated with oxidative phosphorylation. Genes associated with RNA processing were downregulated. In liver regeneration, rapamycin induced genes associated with lysosomal metabolism, steroid metabolism, and the acute phase response. In fetal animals, rapamycin inhibited expression of genes in several functional categories that were unrelated to effects in the adult animals. Translation control showed marked fetal-adult differences. In both adult models, rapamycin inhibited the translation of genes with complex 5= untranslated regions, including those encoding ribosomal proteins. Fetal translation was resistant to the effects of rapamycin. We conclude that the mTOR pathway in liver serves distinct physiological roles in the adult and fetus, with the latter representing a condition of rapamycin resistance.

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confidence: 58%

Section: Discussionmentioning

confidence: 99%

Section: R32mentioning

confidence: 99%

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confidence: 99%

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Profiling of the fetal and adult rat liver transcriptome and translatome reveals discordant regulation by the mechanistic target of rapamycin (mTOR)

Boylan

Sanders

Neretti

et al. 2015

American Journal of Physiology-Regulatory, Integrative and Comp

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“…These signals trigger 4E-BP phosphorylation, which decreases its affinity for eIF4E, freeing it to associate with eIF4G and initiate translation. A major pathway for 4E-BP phosphorylation is the PI3K/Akt/mTORC1 kinase cascade, which is positively regulated by Ras [23][24][25][26] (Fig. 1B).…”

Section: Translational Control Of Cell Fatementioning

confidence: 99%

Translational control of cell fate: From integration of environmental signals to breaching anticancer defense

Bitterman

Polunovsky²

2012

Cell Cycle

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MYC‐binding lncRNA EPIC1 promotes AKT‐mTORC1 signaling and rapamycin resistance in breast and ovarian cancer

Wang

Zhang

Wang

et al. 2020

Molecular Carcinogenesis

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AKT‐mTORC1 (mammalian target of rapamycin complex 1) signaling pathway plays a critical role in tumorigenesis and can be targeted by rapamycin. However, the underlying mechanism of how long noncoding RNA (lncRNAs) regulate the AKT‐mTORC1 pathway remains unclear. EPIC1 (epigenetically‐induced lncRNA 1) is a Myc‐binding lncRNA, which has been previously demonstrated to be overexpressed in multiple cancer types. In a pathway analysis including 4962 cancer patients, we observed that lncRNA EPIC1 expression was positively correlated with the AKT‐mTORC1 signaling pathway in more than 10 cancer types, including breast and ovarian cancers. RNA‐seq analysis of breast and ovarian cancer cells demonstrated that EPIC1‐knockdown led to the downregulation of genes in the AKT‐mTORC1 signaling pathway. In MCF‐7, OVCAR4, and A2780cis cell lines, EPIC1 knockdown and overexpression, respectively, inhibited and activated phosphorylated AKT and the downstream phosphorylation levels of 4EBP1 and S6K. Further knockdown of Myc abolished the EPIC1′s regulation of AKT‐mTORC1 signaling; suggested that the regulation of phosphorylation level of AKT, 4EBP1, and S6K by EPIC1 depended on the expression of Myc. Moreover, EPIC1 overexpressed MCF‐7, A2780cis, and OVCAR4 cells treated with rapamycin showed a significant decreasing in rapamycin mediated inhibition of p‐S6K and p‐S6 comparing with the control group. In addition, Colony Formation assay and MTT assay indicated that EPIC1 overexpression led to rapamycin resistance in breast and ovarian cancer cell lines. Our results demonstrated the lncRNA EPIC1 expression activated the AKT‐mTORC1 signaling pathway through Myc and led to rapamycin resistance in breast and ovarian cancer.

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The physiology and pathophysiology of rapamycin resistance

Cited by 28 publications

References 55 publications

Profiling of the fetal and adult rat liver transcriptome and translatome reveals discordant regulation by the mechanistic target of rapamycin (mTOR)

Profiling of the fetal and adult rat liver transcriptome and translatome reveals discordant regulation by the mechanistic target of rapamycin (mTOR)

Translational control of cell fate: From integration of environmental signals to breaching anticancer defense

MYC‐binding lncRNA EPIC1 promotes AKT‐mTORC1 signaling and rapamycin resistance in breast and ovarian cancer

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