Dysregulation of the mTOR pathway in p53-deficient mice

Leontieva, Olga V.; Novototskaya, Liliya R.; Paszkiewicz, Geraldine; Komarova, Elena A.; Gudkov, Andrei V.; Blagosklonny, Mikhail V.

doi:10.4161/cbt.26947

Cited by 26 publications

(19 citation statements)

References 88 publications

(92 reference statements)

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“…We focused the study on the heart and the liver. Previous reports point to the heart (the cardiac muscle) as to also being very important tissue to measure phospho-S6 (Hua et al ., 2011; Leontieva et al ., 2012a, 2013b; Ramos et al ., 2012; Flynn et al ., 2013; Wu et al ., 2013; Zhou et al ., 2013). The heart is one of the most commonly studied organs in aging, and rapamycin treatment improves the heart condition.…”

Section: Resultsmentioning

confidence: 99%

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Weekly administration of rapamycin improves survival and biomarkers in obese male mice on high‐fat diet

2014

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Recent discoveries have revealed the key role of mTOR (target of rapamycin) in aging. Furthermore, rapamycin extends lifespan in mice, especially in female mice. Here, we treated obese male mice on high-fat diet with rapamycin given intermittently: either weekly (once a week) or alternating bi-weekly (three injections every other week). While only marginally reducing obesity, intermittent administration of rapamycin significantly extended lifespan. Significance was achieved for weekly treated group and for the three rapamycin-received groups combined. In weekly treatment group, 100% mice were alive by the age of 2 years, whereas 60% of mice died in untreated group by this age. The effect of weekly treatment on survival was highly significant and cannot be fully explained by partial reduction in obesity. Alternating bi-weekly treatments seem to be less effective than weekly treatment, although effects of additional factors (see Discussion) may not be excluded. After one year of treatment, all survived mice were sacrificed 8 days after the last administration of rapamycin to avoid its direct interference with parameters examined. Fasting levels of cardiac and hepatic p-S6, a marker of mTORC1 activity, were lower in weekly treatment group compared with control mice. In contrast, levels of p-Akt (S473), glucose, triglycerides and insulin were unchanged, whereas leptin and IGF-1 tended to be lower. Thus, weekly treatment with rapamycin may slow down aging in obese male mice on high-fat diet.

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Section: Resultsmentioning

confidence: 99%

“…Furthermore, cardiovascular diseases are the most common cause of death in humans. Importantly, our previous studies implicate the cardiac phospho-S6 as a potential marker of longevity and animal hypertrophy (Leontieva et al ., 2013b) (Leontieva et al ., 2012a; Flynn et al ., 2013). …”

Section: Resultsmentioning

confidence: 99%

Weekly administration of rapamycin improves survival and biomarkers in obese male mice on high‐fat diet

2014

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“…Second, induction of DNA damage may by itself modulate the mTOR pathway. For example, radiation strongly induced Akt in murine liver, whereas radiation-induced p53 inhibited mTOR downstream (54). We will investigate this special case of unrepaired DNA damage.…”

Section: Discussionmentioning

confidence: 99%

Contact inhibition and high cell density deactivate the mammalian target of rapamycin pathway, thus suppressing the senescence program

Leontieva

Demidenko

Blagosklonny

2014

Proc. Natl. Acad. Sci. U.S.A.

127

117

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Significance This work solves longstanding mysteries in the field of contact inhibition (CI), cancer, and aging. As shown here during CI, cells do not undergo senescence, thus resuming proliferation after replating. We found that CI was associated with inhibition of the mammalian target of rapamycin (mTOR) pathway, which is required for the senescence program. In cancer cells, lacking CI, mTOR was still inhibited in high cell density by an alternative mechanism. Our work explains why CI is reversible and how cells can avoid senescence in vivo, allowing the organism to last for decades. Implications for cancer therapy are discussed.

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“…It was reported that radiation induced Thr308 Akt phosphorylation in the livers of both p53 wild-type and knockout mice. However, radiation decreased phospho-S6 kinase in the livers of p53 wild-type mice, and had the negative effect of p53 on mTOR [38]. Radiation induced tumor suppressor p53 is involved in the complex response to radiation, including cell cycle regulation, DNA repair, and apoptosis [39, 40].…”

Section: Discussionmentioning

confidence: 99%

Targeting Phosphatidylinositide3-Kinase/Akt pathway by BKM120 for radiosensitization in hepatocellular carcinoma

Gao

Tzen

et al. 2014

Oncotarget

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Tumor control of hepatocellular carcinoma by radiotherapy remains unsatisfactory. The phosphatidylinositol 3-kinase (PI3K)/Akt pathway plays a critical role in inhibiting cancer cell death. Elevated PI3K/Akt activity is associated with increased cellular resistance to irradiation. Our aim was to determine whether the inhibition of PI3K/Akt activity by a PI3K inhibitor, BKM120, contributes to the increased sensitivity of liver cancer cells to irradiation. The hepatocellular carcinoma cell lines (Huh7 and BNL) were used to evaluate the in vitro synergism between BKM120 and irradiation. Balb/c mice bearing ectopic BNL xenografts were treated with BKM120 and/or radiotherapy to assess the in vivo response. BKM120 increased cell killing by radiation, increased the expression of apoptotic markers, and suppressed the repair of radiation-induced DNA double-strand breaks. BKM120 pretreatment inhibited radiation-induced Akt phosphorylation and enhanced the tumor-suppressive effect and radiation-induced tumor cell apoptosis in ectopic xenografts. Inhibition of mTOR phosphorylation by rapamycin enhanced the radiosensitivity of BKM120-treated hepatocellular carcinoma cells. The synergism between BKM120 and irradiation likely inhibits the activation of Akt by radiation, leading to increased cell apoptosis and suppression of DNA-double-strand breaks repair in hepatocellular carcinoma cells. These data suggest that the BKM120/radiation combination may be a strategy worthy of clinical trials.

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Dysregulation of the mTOR pathway in p53-deficient mice

Cited by 26 publications

References 88 publications

Weekly administration of rapamycin improves survival and biomarkers in obese male mice on high‐fat diet

Weekly administration of rapamycin improves survival and biomarkers in obese male mice on high‐fat diet

Contact inhibition and high cell density deactivate the mammalian target of rapamycin pathway, thus suppressing the senescence program

Targeting Phosphatidylinositide3-Kinase/Akt pathway by BKM120 for radiosensitization in hepatocellular carcinoma

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