Modulation of the EMT/MET process by pyrrole–imidazole polyamide targeting human transforming growth factor-β1

Saito, Kosuke; Fukuda, Noboru; Shinohara, Ken‐ichi; Masuhiro, Yoshikazu; Hanazawa, Shigemasa; Matsuda, Hiroyuki; Fujiwara, Kyoko; Ueno, Takayoshi; Soma, Masayoshi

doi:10.1016/j.biocel.2015.07.011

Cited by 5 publications

(5 citation statements)

References 39 publications

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“…Prior studies have suggested that TGF-β activation increases the expression of Snail family proteins and decreases the expression of E-cadherin, resulting in EMT. In contrast, the inhibition of TGF-β signaling has been demonstrated to downregulate Snail family proteins and increases the expression of E-cadherin, resulting in the epithelial phenotype in human epithelial cells [ 54 ].…”

Section: Discussionmentioning

confidence: 99%

Withaferin-A suppress AKT induced tumor growth in colorectal cancer cells

et al. 2016

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The oncogenic activation of AKT gene has emerged as a key determinant of the aggressiveness of colorectal cancer (CRC); hence, research has focused on targeting AKT signaling for the treatment of advanced stages of CRC. In this study, we explored the anti-tumorigenic effects of withaferin A (WA) on CRC cells overexpressing AKT in preclinical (in vitro and in vivo) models. Our results indicated that WA, a natural compound, resulted in significant inhibition of AKT activity and led to the inhibition of cell proliferation, migration and invasion by downregulating the epithelial to mesenchymal transition (EMT) markers in CRC cells overexpressing AKT. The oral administration of WA significantly suppressed AKT-induced aggressive tumor growth in a xenograft model. Molecular analysis revealed that the decreased expression of AKT and its downstream pro-survival signaling molecules may be responsible for tumor inhibition. Further, significant inhibition of some important EMT markers, i.e., Snail, Slug, β-catenin and vimentin, was observed in WA-treated human CRC cells overexpressing AKT. Significant inhibition of micro-vessel formation and the length of vessels were evident in WA-treated tumors, which correlated with a low expression of the angiogenic marker RETIC. In conclusion, the present study emphasizes the crucial role of AKT activation in inducing cell proliferation, angiogenesis and EMT in CRC cells and suggests that WA may overcome AKT-induced cell proliferation and tumor growth in CRC.

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Section: Discussionmentioning

confidence: 99%

Withaferin-A suppress AKT induced tumor growth in colorectal cancer cells

et al. 2016

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“…110 In addition, SIRT7 plays a regulatory role in the process of mesenchymal-to-epithelial transition (MET) ( Table 1), which has been suggested to be a crucial process in the generation of iPSCs from fibroblasts. 111,112 However, more studies are required to prove that SIRT7 actually regulates the EMT and MET processes, respectively (Figure 1).…”

Section: Sirt7mentioning

confidence: 99%

Current understanding and future perspectives of the roles of sirtuins in the reprogramming and differentiation of pluripotent stem cells

Hsu

Tsai

et al. 2018

Exp Biol Med (Maywood)

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In mammalian cells, there are seven members of the sirtuin protein family (SIRT1-7). SIRT1, SIRT6, and SIRT7 catalyze posttranslational modification of proteins in the nucleus, SIRT3, SIRT4, and SIRT5 are in the mitochondria and SIRT2 is in the cytosol. SIRT1 can deacetylate the transcription factor SOX2 and regulate induced pluripotent stem cells (iPSCs) reprogramming through the miR-34a-SIRT1-p53 axis. SIRT2 can regulate the function of pluripotent stem cells through GSK3β. SIRT3 can positively regulate PPAR gamma coactivator 1-alpha (PGC-1α) expression during the differentiation of stem cells. SIRT4 has no direct role in regulating reprogramming but may have the potential to prevent senescence of somatic cells and to facilitate the reprogramming of iPSCs. SIRT5 can deacetylate STAT3, which is an important transcription factor in regulating pluripotency and differentiation of stem cells. SIRT6 can enhance the reprogramming efficiency of iPSCs from aged skin fibroblasts through miR-766 and increase the expression levels of the reprogramming genes including Sox2, Oct4, and Nanog through acetylation of histone H3 lysine 56. SIRT7 plays a regulatory role in the process of mesenchymal-to-epithelial transition (MET), which has been suggested to be a crucial process in the generation of iPSCs from fibroblasts. In this review, we summarize recent findings of the roles of sirtuins in the metabolic reprogramming and differentiation of stem cells and discuss the bidirectional changes in the gene expression and activities of sirtuins in the commitment of differentiation of mesenchymal stem cells (MSCs) and reprogramming of somatic cells to iPSCs, respectively. Thus, understanding the molecular basis of the interplay between different sirtuins and mitochondrial function will provide new insights into the regulation of differentiation of stem cells and iPSCs formation, respectively, and may help design effective stem cell therapies for regenerative medicine. Impact statement This is an extensive review of the recent advances in our understanding of the roles of some members of the sirtuins family, such as SIRT1, SIRT2, SIRT3, and SIRT6, in the regulation of intermediary metabolism during stem cell differentiation and in the reprogramming of somatic cells to form induced pluripotent stem cells (iPSCs). This article provides an updated integrated view on the mechanisms by which sirtuins-mediated posttranslational protein modifications regulate mitochondrial biogenesis, bioenergetics, and antioxidant defense in the maintenance and differentiation of stem cells and in iPSCs formation, respectively.

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“…The role of TGF‐β in promoting liver fibrosis is primarily mediated by activating HSCs 10 . However, the effect of TGF‐β signaling in hepatocytes on liver fibrosis remains controversial.…”

Section: Introductionmentioning

confidence: 99%

“…The role of TGF-β in promoting liver fibrosis is primarily mediated by activating HSCs. 10 However, the effect of TGF-β signaling in hepatocytes on liver fibrosis remains controversial. Dooley et al revealed that attenuating the TGF-β signaling pathway in hepatocytes with hepatocyte-specific Smad7 overexpression reduced hepatic collagen deposition and improved CCl 4 -induced liver fibrosis.…”

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confidence: 99%

Depletion of Tgfbr2 in hepatocytes alleviates liver fibrosis and restores hepatic function in fibrotic mice

Liu

Deng

Zhu

et al. 2023

J of Digest Diseases

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Objectives: Previous studies have demonstrated the pivotal role of transforming growth factor (TGF)-β signaling in activating hepatic stellate cells during liver fibrosis. In this study we aimed to demonstrate the effects and underlying mechanism of TGF-β signaling in hepatocytes on hepatic fibrogenesis.Methods: Hepatocyte-specific Tgfbr2-knockout (Tgfbr2 HKO ) mice were generated by AAV8-TBG-Cre injection via the tail vein of Tgfbr2 f/f mice. CCl 4 was injected intraperitoneally twice a week for 4 weeks to establish the fibrotic mouse model. The expression of the fibrogenesis markers was evaluated by immunohistochemistry, western blot, and real-time polymerase chain reaction (PCR). RNA-seq analysis was used to detect the transcriptional profiles of primary hepatocytes isolated from Tgfbr2 HKO mice and control mice. Results:The expression of TβR2 (Tgfbr2) was markedly upregulated in hepatocytes of the fibrotic liver. Tgfbr2 depletion in hepatocytes decreased the expressions of profibrogenic markers (Col1a1 and Acta2) in the CCl 4 -treated fibrotic liver. RNA-seq analysis revealed that Tgfbr2 deletion in hepatocytes significantly reduced the inflammatory response and suppressed epithelial-mesenchymal transition of hepatocytes accompanied by upregulation of the metabolic pathways during liver fibrosis.Moreover, the expressions of hepatocyte nuclear factors (HNFs), including Hnf4α, Foxa1, Foxa2, and Foxa3, which are important for maintaining liver metabolism and homeostasis, were decreased in fibrotic livers and significantly increased after Tgfbr2 blockade. Conclusion:Blocking the TGF-β signaling pathway in hepatocytes reduces hepatic fibrosis and improves hepatic function in fibrotic livers.

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Modulation of the EMT/MET process by pyrrole–imidazole polyamide targeting human transforming growth factor-β1

Cited by 5 publications

References 39 publications

Withaferin-A suppress AKT induced tumor growth in colorectal cancer cells

Withaferin-A suppress AKT induced tumor growth in colorectal cancer cells

Current understanding and future perspectives of the roles of sirtuins in the reprogramming and differentiation of pluripotent stem cells

Depletion of Tgfbr2 in hepatocytes alleviates liver fibrosis and restores hepatic function in fibrotic mice

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