Rapamycin delays tumor development in murine livers by inhibiting proliferation of hepatocytes with DNA damage

Buitrago‐Molina, Laura Elisa; Pothiraju, D.; Lamlé, Jutta; Marhenke, Silke; Kossatz-Boehlert, Uta; Breuhahn, Kai; Manns, Michael P.; Malek, Nisar P.; Vogel, Arndt

doi:10.1002/hep.23014

Cited by 39 publications

(41 citation statements)

References 21 publications

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“…The allosteric mTOR inhibitor rapamycin is known to significantly delay S phase entry and liver regeneration, indicating an important functional role for mTOR signaling (15)(16)(17). We show here that treatment with rapamycin derivatives severely blunts phosphorylation of the mTORC1 substrates S6K1 and S6K2, while having no effect on the 4E-BP family members of mTORC1 substrates and upregulating the activity of the mTORC2 substrates Akt1-Akt3 (Figure 1).…”

Section: Discussionmentioning

confidence: 69%

“…Between 36 to 42 hours after twothirds PH, most hepatocytes are in the S phase of the cell cycle, after having entered the cell cycle by transitioning from the G 0 into the G 1 phase, passed the restriction point in late G 1 , and initiated DNA replication. Since rapamycin treatment causes a significant delay in S phase entry of hepatocytes after hepatectomy (15)(16)(17), we set out here to study rapamycin-sensitive mechanisms that intervene during liver regeneration. We compare pharmacologic treatments and genetic invalidation of S6K and Akt family members.…”

Section: Introductionmentioning

confidence: 99%

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S6 kinase 1 is required for rapamycin-sensitive liver proliferation after mouse hepatectomy

et al. 2011

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Rapamycin is an antibiotic inhibiting eukaryotic cell growth and proliferation by acting on target of rapamycin (TOR) kinase. Mammalian TOR (mTOR) is thought to work through 2 independent complexes to regulate cell size and cell replication, and these 2 complexes show differential sensitivity to rapamycin. Here we combine functional genetics and pharmacological treatments to analyze rapamycin-sensitive mTOR substrates that are involved in cell proliferation and tissue regeneration after partial hepatectomy in mice. After hepatectomy, hepatocytes proliferated rapidly, correlating with increased S6 kinase phosphorylation, while treatment with rapamycin derivatives impaired regeneration and blocked S6 kinase activation. In addition, genetic deletion of S6 kinase 1 (S6K1) caused a delay in S phase entry in hepatocytes after hepatectomy. The proliferative defect of S6K1-deficient hepatocytes was cell autonomous, as it was also observed in primary cultures and hepatic overexpression of S6K1-rescued proliferation. We found that S6K1 controlled steady-state levels of cyclin D1 (Ccnd1) mRNA in liver, and cyclin D1 expression was required to promote hepatocyte cell cycle. Notably, in vivo overexpression of cyclin D1 was sufficient to restore the proliferative capacity of S6K-null livers. The identification of an S6K1-dependent mechanism participating in cell proliferation in vivo may be relevant for cancer cells displaying high mTOR complex 1 activity and cyclin D1 accumulation.

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Section: Discussionmentioning

confidence: 69%

Section: Introductionmentioning

confidence: 99%

S6 kinase 1 is required for rapamycin-sensitive liver proliferation after mouse hepatectomy

et al. 2011

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“…Specifically, roxithromycin, SAR943, a rapamycin analog, as well as rapamycin itself inhibit the proliferation of human coronary artery SMCs, 18 epithelial and airway SMCs, 19 and rapamycin also inhibits the proliferation of hepatocytes. 20 Other macrolides such as erythromycin have been shown to inhibit hypertrophic and metaplastic changes of goblet cells in rat nasal epithelium, as well as inhibit the proliferation of human mononuclear cells. 21,22 Azithromycin along with clarithromycin are reported to induce apoptosis of activated lymphocytes.…”

Section: Discussionmentioning

confidence: 99%

Azithromycin reduces the viability of human bronchial smooth muscle cells

et al. 2010

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The macrolide antibiotic azithromycin has an antiproliferative and autophagic effect on rabbit tracheal smooth muscle cells (SMCs). The purpose of this study is to investigate the effect of azithromycin on human bronchial SMCs. Human bronchial SMCs were treated with azithromycin (10 À5 M) in the presence or absence of 10% fetal bovine serum (FBS). Cell number was estimated using the Cell Titer 96 AQ ueous One Solution Assay. Induction of autophagy was studied by observation of cell morphology in cells treated or not with the autophagy inhibitor, 3-methyladenine (3-MA), as well as by Lysotracker Red staining of lysosomes. Activation of apoptosis was assessed with flow cytometry after annexin staining. Incubation with azithromycin for 24, 48 or 72 h reduced viability in FBS-deprived cells, as well as cells cultured in FBS-containing medium. Azithromycin treatment resulted in the formation of cytoplasmic vacuoles that could not be prevented by 3-MA. Furthermore, 3-MA did not reverse the effect of azithromycin on the viability of SMCs. There was an increase in the number of lysosomes in cells treated with azithromycin. Finally, azithromycin increased the percentage of early apoptotic cells. In conclusion, azithromycin reduces the viability of human bronchial SMCs possibly by leading to apoptotic cell death.

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“…For example, RAD001 (a rapalog) suppressed hepatocyte proliferation during chronic liver injury that was dependent on p53. 39 Further, RAD001 combined with cisplatin suppressed the growth of hepatocellular carcinoma cells, which was enhanced by p53 expression. 40 Another genotoxin, doxorubicin, caused acute cardiac dysfunction and reduced cardiac mass through p53-dependent mTOR inhibition.…”

Section: P53 Inhibits Mtorc1 To Suppressmentioning

confidence: 95%