Tumour suppressors of the Forkhead box O (FoxO) family are proposed to limit tumour growth through direct transcriptional regulation. Cytosolic FoxO1 can also suppress tumour growth by triggering autophagy and ultimately cell death in a transcription-independent manner.
"However, part of HDAC effects is independent of the nucleus, for example, FOXO (Forkhead box O) transcriptional protein family members, including FOXO1 and FOXO3. Cytosolic FOXO1 was reported to suppress tumor growth by triggering autophagy . In response to stress, FOXO1 could be acetylated by SIRT2 and the acetylated FoxO1 bound to Atg7 to influence the autophagic process leading to cell death . "
"Recently, some of the FoxO1 and FoxO3A target genes were shown to be involved in autophagic protection of skeletal myocytes, cardiomyocytes and neurons from stress conditions (Hariharan et al, 2010; Masiero et al, 2009; Medema & Jaattela, 2010; Sengupta et al, 2009; van der Vos et al, 2011; Xu et al, 2011; Zhao et al, 2007). Autophagy can also be induced by intracellular stresses that are involved in the pathogenesis of diabetic nephropathy including hypoxia or ER stress (Kume et al, 2012; Mizushima & Komatsu, 2011), and plays an important role as a survival factor especially in post-mitotic cells such as podocytes (Fogo, 2011; Godel et al, 2011; Hartleben et al, 2010; He et al, 2010; Inoki et al, 2011; Kume et al, 2010; Nath, 2010). "
[Show abstract][Hide abstract] ABSTRACT: ADAM17 and its inhibitor TIMP3 are involved in nephropathy, but their role in diabetic kidney disease (DKD) is unclear. Diabetic Timp3−/− mice showed increased albuminuria, increased membrane thickness and mesangial expansion. Microarray profiling uncovered a significant reduction of Foxo1 expression in diabetic Timp3−/− mice compared to WT, along with FoxO1 target genes involved in autophagy, while STAT1, a repressor of FoxO1 transcription, was increased. Re-expression of Timp3 in Timp3−/− mesangial cells rescued the expression of Foxo1 and its targets, and decreased STAT1 expression to control levels; abolishing STAT1 expression led to a rescue of FoxO1, evoking a role of STAT1 in linking Timp3 deficiency to FoxO1. Studies on kidney biopsies from patients with diabetic nephropathy confirmed a significant reduction in TIMP3, FoxO1 and FoxO1 target genes involved in autophagy compared to controls, while STAT1 expression was strongly increased.
Our study suggests that loss of TIMP3 is a hallmark of DKD in human and mouse models and designates TIMP3 as a new possible therapeutic target for diabetic nephropathy.
EMBO Molecular Medicine 03/2013; 5(3). DOI:10.1002/emmm.201201475 · 8.67 Impact Factor
"The above results suggested that resveratrol can directly induce the expression of the tumor suppressor gene FoxO1, thereby leading to the suppression of the tumor growth and cell death by triggering autophagy , . IL-2 can facilitate such effects by the unknown factors from the HDIL-2-induced inflammation. "
[Show abstract][Hide abstract] ABSTRACT: Immunotherapy with high-dose interleukin-2 (HDIL-2) is an effective treatment for patients with metastatic melanoma and renal cell carcinoma. However, it is accompanied by severe toxicity involving endothelial cell injury and induction of vascular leak syndrome (VLS). In this study, we found that resveratrol, a plant polyphenol with anti-inflammatory and anti-cancer properties, was able to prevent the endothelial cell injury and inhibit the development of VLS while improving the efficacy of HDIL-2 therapy in the killing of metastasized melanoma. Specifically, C57BL/6 mice were injected with B16F10 cells followed by resveratrol by gavage the next day and continued treatment with resveratrol once a day. On day 9, mice received HDIL-2. On day 12, mice were evaluated for VLS and tumor metastasis. We found that resveratrol significantly inhibited the development of VLS in lung and liver by protecting endothelial cell integrity and preventing endothelial cells from undergoing apoptosis. The metastasis and growth of the tumor in lung were significantly inhibited by HDIL-2 and HDIL-2 + resveratrol treatment. Notably, HDIL-2 + resveratrol co-treatment was more effective in inhibiting tumor metastasis and growth than HDIL-2 treatment alone. We also analyzed the immune status of Gr-1(+)CD11b(+) myeloid-derived suppressor cells (MDSC) and FoxP3(+)CD4(+) regulatory T cells (Treg). We found that resveratrol induced expansion and suppressive function of MDSC which inhibited the development of VLS after adoptive transfer. However, resveratrol suppressed the HDIL-2-induced expansion of Treg cells. We also found that resveratrol enhanced the susceptibility of melanoma to the cytotoxicity of IL-2-activated killer cells, and induced the expression of the tumor suppressor gene FoxO1. Our results suggested the potential use of resveratrol in HDIL-2 treatment against melanoma. We also demonstrated, for the first time, that MDSC is the dominant suppressor cell than regulatory T cell in the development of VLS.
PLoS ONE 04/2012; 7(4):e35650. DOI:10.1371/journal.pone.0035650 · 3.23 Impact Factor
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