Temporal mTOR inhibition protects Fbxw7-deficient mice from radiation-induced tumor development

Liu, Yueyong; Huang, Yurong; Wang, Zeran; Huang, Yong; Li, Xiaohua; Louie, Alexander; Wei, Guangwei; Mao, Jian-Hua

doi:10.18632/aging.100535

Cited by 19 publications

(19 citation statements)

References 27 publications

(37 reference statements)

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“…Considering the positive correlation between mTOR and ZEB1 in CCA demonstrated in this study, mTOR inhibitor may be a potential therapeutic strategy to increase the chemotherapy sensitivity and effectiveness of CCA. Liu et.al [38] revealed temporal mTOR inhibition protected Fbxw7-deficient mice from radiation-induced tumor development. Of note, Liza C. et.al [39] reported a lung adenocarcinoma patient with FBXW7 deficiency both clinically and radiographically benefited from treatment with the mTOR inhibitor.…”

Section: Discussionmentioning

confidence: 99%

FBXW7 suppresses epithelial-mesenchymal transition, stemness and metastatic potential of cholangiocarcinoma cells

Yang

Liu³

et al. 2015

Oncotarget

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Epithelial-mesenchymal transition (EMT) plays a fundamental role in cancer metastasis. The ubiquitin ligase FBXW7, a general tumor suppressor in human cancer, has been implicated in diverse cellular processes, however, its role in cholangiocarcinoma (CCA) metastasis has not been identified. Here, we report a crucial role of FBXW7 in CCA metastasis by regulating EMT. Loss of FBXW7 expression was detected in CCA cells and clinical specimens. Clinicopathological analysis revealed a close correlation between FBXW7 deficiency and metastasis, TNM stage and differentiation in intrahepatic CCA and perihilar CCA. Moreover, FBXW7 silencing in CCA cells dramatically promoted EMT, stem-like capacity and metastasis both in vitro and in vivo. Conversely, FBXW7 overexpression attenuated these processes. Mechanistically, treatment with rapamycin, a mTOR inhibitor, inhibited EMT, stem-like capacity and metastasis induced by FBXW7 silencing both in vitro and in vivo. Furthermore, the expression of EMT regulating transcription factors, snail, slug and ZEB1, were also decreased markedly with rapamycin treatment. In addition, silencing ZEB1 inhibited EMT and metastasis of both CCA cells and FBXW7 deficient CCA cells, which implicated the potential role of ZEB1 in FBXW7/mTOR signaling pathway related CCA metastasis. In conclusion, our findings defined a pivotal function of FBXW7 in CCA metastasis by regulating EMT.

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Section: Discussionmentioning

confidence: 99%

FBXW7 suppresses epithelial-mesenchymal transition, stemness and metastatic potential of cholangiocarcinoma cells

Yang

Liu³

et al. 2015

Oncotarget

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“…mTOR is the key molecule that regulates cancer growth and the process of aging both in the presence or absence of CR [37]. Inhibition of mTOR by rapamycin has been extensively shown to extend life span and retard cancer growth in various genetic models that include Rb+/−, p53+/−, p53−/− and Fbwx7−/− [84-87]. These studies underline the pivotal role of mTOR in the process of carcinogenesis irrespective of the tumor type or etiology.…”

Section: Discussionmentioning

confidence: 99%

Dietary energy balance modulates ovarian cancer progression and metastasis

et al. 2014

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A high energy balance, or caloric excess, accounts as a tumor promoting factor, while a negative energy balance via caloric restriction, has been shown to delay cancer progression. The effect of energy balance on ovarian cancer progression was investigated in an isogeneic immunocompetent mouse model of epithelial ovarian cancer kept on a regimen of regular diet, high energy diet (HED) and calorie restricted diet (CRD), prior to inoculating the animals intraperitoneally with the mouse ovarian surface epithelial ID8 cancer cells. Tumor evaluation revealed that mice group on HED displayed the most extensive tumor formation with the highest tumor score at all organ sites (diaphragm, peritoneum, bowel, liver, kidney, spleen), accompanied with increased levels of insulin, leptin, insulin growth factor-1 (IGF-1), monocyte chemoattractant protein-1 (MCP-1), VEGF and interleukin 6 (IL-6). On the other hand, the mice group on CRD exhibited the least tumor burden associated with a significant reduction in levels of insulin, IGF-1, leptin, MCP-1, VEGF and IL-6. Immunohistochemistry analysis of tumors from HED mice showed higher activation of Akt and mTOR with decreased adenosine monophosphate activated kinase (AMPK) and SIRT1 activation, while tumors from the CRD group exhibited the reverse profile. In conclusion, ovarian cancer growth and metastasis occurred more aggressively under HED conditions and was significantly curtailed under CRD. The suggested mechanism involves modulated secretion of growth factors, cytokines and altered regulation of AMPK and SIRT1 that converges on mTOR inhibition. While the role of a high energy state in ovarian cancer has not been confirnmed in the literature, the current findings support investigating the potential impact of diet modulation as adjunct to other anticancer therapies and as possible individualized treatment strategy of epithelial ovarian cancer.

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“…Keeping abreast with this finding, Mao et al subsequently reported that FBW7 mediates the critical role of p53 in response to DNA damage, indicating that FBW7 gene is a p53-dependent tumor suppressor gene involved in tumorigeneis [89]. Furthermore, this group found that inhibition of mTOR signaling pathway by rapamycin after exposure to radiation retarded tumor development in FBW7/p53 double heterozygous mice [104]. Taken together, these studies showed that targeting the p53 signaling pathway could potentially influence FBW7 expression, which might provide a feasible approach to restore FBW7 expression for anti-cancer therapies.…”

Section: Introductionmentioning

confidence: 99%

Aberrant regulation of FBW7 in cancer

Wang

Ye²,

Liu³

et al. 2014

Oncotarget

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FBW7 (F-box and WD repeat domain-containing 7) or Fbxw7 is a tumor suppressor, which promotes the ubiquitination and subsequent degradation of numerous oncoproteins including Mcl-1, Cyclin E, Notch, c- Jun, and c-Myc. In turn, FBW7 is regulated by multiple upstream factors including p53, C/EBP-δ, EBP2, Pin1, Hes-5 and Numb4 as well as by microRNAs such as miR-223, miR-27a, miR-25, and miR-129-5p. Given that the Fbw7 tumor suppressor is frequently inactivated or deleted in various human cancers, targeting FBW7 regulators is a promising anti-cancer therapeutic strategy.

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Temporal mTOR inhibition protects Fbxw7-deficient mice from radiation-induced tumor development

Cited by 19 publications

References 27 publications

FBXW7 suppresses epithelial-mesenchymal transition, stemness and metastatic potential of cholangiocarcinoma cells

FBXW7 suppresses epithelial-mesenchymal transition, stemness and metastatic potential of cholangiocarcinoma cells

Dietary energy balance modulates ovarian cancer progression and metastasis

Aberrant regulation of FBW7 in cancer

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