TGF-β1 regulates cell fate during epithelial–mesenchymal transition by upregulating survivin

Abstract

Members of the transforming growth factor beta (TGF-β) superfamily are multifunctional cytokines that regulate several cellular processes, including cell cycle arrest, differentiation, morphogenesis, and apoptosis. TGF-β promotes extracellular matrix production and morphological change. Morphogenetic responses to TGF-β include cell migration and epithelial–mesenchymal transition (EMT), which are critical during embryogenesis, development of fibrotic diseases, and the spreading of advanced carcinomas. The purpose of this study was to clarify how TGF-β regulates the fate of retinal pigment epithelial (RPE) cells. TGF-β1 promoted cell cycle progression and phosphorylation of retinoblastoma protein (Rb) in ARPE-19 cells. TGF-β1 induced survivin expression, which in turn stabilized tubulin and Aurora B. RT-PCR and western blot analysis revealed that survivin expression increased in ARPE-19 cells following TGF-β1 treatment. When survivin was depleted, TGF-β1 induced cell cycle arrest and apoptosis and also reduced Rb phosphorylation. In conclusion, the present study shows that induction of EMT in human RPE cells upregulates survivin, leading to survivin-dependent inhibition of cell cycle arrest and apoptosis. Whether cells undergo EMT or apoptosis in response to TGF-β1 is dependent on their cell cycle state, and TGF-β1 regulates the cell cycle via survivin.

Sustainability of CD24 expression, cell proliferation and migration, cisplatin-resistance, and caspase-3 expression during mesenchymal-epithelial transition induced by the removal of TGF-β1 in A549 lung cancer cells

“…It is difficult to rationalise the inconsistency between studies; however, the types of cell line, media and extra-and intracellular conditions are among the variables that may contribute to these differences. Concerning the apoptosis mechanism, it was reported that treatment with TGF-β1 may increase survivin, which promotes cell cycle progression and inhibits apoptosis during EMT (31). The results of the present study demonstrated that the active form of caspase-3 was decreased and G2/M phase cells were increased in the TGF-β1-treated and MET/return groups.…”

The concomitant apoptosis and EMT underlie the fundamental functions of TGF-β

“…Nevertheless, the molecular mechanism of the concomitant apoptosis and EMT remains to be characterized. In retinal pigment epithelial (RPE) cells, survivin was shown to be involved in the control of the TGF-β-mediated cell cycle state, which is important for the induction of EMT [64]. Strikingly, in TGF-β-induced concomitant apoptosis and EMT, certain molecules, such as PKA and STAT3 [34], NOS/NO [42], AMPK [65], and p38 MAP kinase [66][67][68][69], are required for both events.…”

Phenotypic plasticity and epithelial‐to‐mesenchymal transition in the behaviour and therapeutic response of oral squamous cell carcinoma

“…Additionally, N‐cadherin is upregulated during EMT as E‐cadherin is downregulated, the ‘cadherin switch’ . TGFβ also mediates other properties of EMT cells, such as anti‐apoptosis, whereas in non‐EMT cells, it can have a pro‐apoptotic role . Other pathways involved in EMT involve hypoxia‐inducible factor (HIF), which not only induces Twist and Snail expression, but also positively impacts upon pro‐EMT β‐catenin.…”