Rapamycin-Induced Apoptosis in HGF-Stimulated Lens Epithelial Cells by AKT/mTOR, ERK and JAK2/STAT3 Pathways

Abstract

Hepatocyte growth factor (HGF) induced the proliferation of lens epithelial cells (LECs) and may be a major cause of posterior capsule opacification (PCO), which is the most frequent postoperative complication of cataract surgery. To date, several agents that can block LECs proliferation have been studied, but none have been used in clinic. Recently, accumulating evidence has suggested rapamycin, the inhibitor of mTOR (mammalian target of Rapamycin), was associated with the induction of apoptosis in LECs. The purpose of our study was to investigate the potential effects of rapamycin on HGF-induced LECs and the underlying mechanisms by which rapamycin exerted its actions. Using cell proliferation, cell viability and flow cytometric apoptosis assays, we found that rapamycin potently not only suppressed proliferation but also induced the apoptosis of LECs in a dose-dependent manner under HGF administration. Further investigation of the underlying mechanism using siRNA transfection revealed that rapamycin could promote apoptosis of LECs via inhibiting HGF-induced phosphorylation of AKT/mTOR, ERK and JAK2/STAT3 signaling molecules. Moreover, the forced expression of AKT, ERK and STAT3 could induce a significant suppression of apoptosis in these cells after treatment of rapamycin. Together, these findings suggested that rapamycin-induced apoptosis in HGF-stimulated LECs is accompanied by inhibition of AKT/mTOR, ERK and JAK2/STAT3 pathways, which supports its use to inhibit PCO in preclinical studies and provides theoretical foundation for future possible practice.

Autophagy is involved in ethanol-induced cardia bifida during chick cardiogenesis

“…RAPA has been demonstrated to activate autophagy in epithelial cells. 34 In previous study, 32 we discovered that RAPA treatment promoted the expression of ATG7, and Atg7-mediated autophagy did appear in the gastrulation stage of early embryonic development. We incubated chick embryos (HH0) in the presence of 40nM of RAPA until they reached stage HH11, when the heart tube has formed.…”

<p>KLF6 Induces Apoptosis in Human Lens Epithelial Cells Through the ATF4-ATF3-CHOP Axis</p>

“…UV radiation, aging, hypoxia, and other stimuli could cause excess apoptosis of lens epithelial cells, thus causing cytoskeletal degradation, accumulation of crystal protein, and ultimately cataract. 37 It has been approved that the apoptosis of lens epithelial cells is much more different in high myopia cataract and ordinary age-related cataract patients. We analyzed lens capsule gene microarray data in high myopia patients and identified two differentially expressed genes: Krüppellike factor 6 (KLF6) and ATF4.…”

“…This experiment was repeated 3 times. 37,38,39 Statistics All data were expressed as mean±SD. All experiments were performed at least three times.…”

Paraquat Induces Apoptosis through Cytochrome C Release and ERK Activation

“…Many prior studies have provided evidence indicating that the ERK1/2 pathway is regulated mostly by mitogenic stimuli, and leads to the production of proteins required for cell growth and differentiation ( Craig et al ., 2008 ; Kim and Choi, 2010 ; Munshi and Ramesh, 2013 ). However, more recently, several studies have demonstrated that inhibition of ERK signaling leads to increased sensitivity of anticancer drug ( Ohmichi et al ., 2005 ; Tian et al ., 2014a ; Tian et al ., 2014b ). ERK activation induces the deveploment of B cell ( Gold, 2008 ) and activation of ERK is also involved in the inducation of apoptosis in neuronal and various cancer cells ( Agrawal et al ., 2014 ; Deschenes-Simard et al ., 2014 ; Esmaeili et al ., 2014 ).…”