MTORC1 regulates apoptosis and cell proliferation in pterygium via targeting autophagy and FGFR3

Yanli Liu,Hanchun Xu,Meixia An

doi:10.1038/s41598-017-07844-y

Abstract

Pterygium is one of the most common ocular surface diseases. During the initiation of pterygium, resting epithelial cells are activated and exhibit aberrant apoptosis and cell proliferation. Mechanistic target of rapamycin complex 1 (mTORC1) is a central regulator of cell growth, cell proliferation, protein synthesis, autophagy and transcription. However, the effect of mTORC1 activation in epithelial cells on pterygium development has not yet been reported. Additionally, the roles of mTORC1 in aberrant apoptosis and cell proliferation during the initiation of pterygium, and the underlying mechanisms, are not known. Herein, we evaluated mTOR signalling in pterygium growth and development. The results revealed that mTOR signalling, especially mTORC1 signaling, is highly activated, and aberrant apoptosis and cell proliferation were observed in pterygium. mTORC1 activation inhibits apoptosis in pterygium by regulating Beclin 1-dependent autophagy via targeting Bcl-2. mTORC1 also negatively regulates fibroblast growth factor receptor 3 (FGFR3) through inhibition of p73, thereby stimulating cell proliferation in pterygium. These data demonstrate that mTORC1 signalling is highly activated in pterygium and provide new insights into the pathogenesis and progression of pterygium. Hence, mTORC1 may be a novel therapeutic target for the treatment of pterygium.

Highlights

Pterygium is a common ocular surface disease that leads to corneal astigmatism, dyskinesia and even vision loss
Mammalian target of rapamycin is an important suppressor of autophagy and regulator of cell metabolism. mTOR forms two distinct multiprotein complexes: mammalian target of rapamycin complex 1 and mTORC2. mTOR interacts with Raptor, mLst8/GbL, Deptor, and PRAS40, thereby forming mTOR complex 1. mTORC1 is a sensitive target of rapamycin and integrates input from many upstream signals, including insulin, growth factors, amino acids, oxygen, and energy levels, mTORC1 is a central regulator of cell growth, cell proliferation, cell motility, cell survival, protein synthesis, autophagy and transcription[5]
We propose a pathway in which mTORC1 activation downregulates autophagy and fibroblast growth factor receptor 3 (FGFR3) in pterygium epithelial cells, inhibiting apoptosis, stimulating cell proliferation, and promoting pterygium growth and development. mTORC1 signalling - control of autophagy and FGFR3 is a critical regulator of pterygium epithelial cell metabolism and a potential target for pterygium treatment (Fig. 6)

Summary

Introduction

Pterygium is a common ocular surface disease that leads to corneal astigmatism, dyskinesia and even vision loss. More considerable progress must be made towards understanding the mechanisms responsible for regulating pterygium epithelial apoptosis and cell proliferation. Mammalian target of rapamycin (mTOR) is an important suppressor of autophagy and regulator of cell metabolism. MTORC1 is a sensitive target of rapamycin and integrates input from many upstream signals, including insulin, growth factors, amino acids, oxygen, and energy levels, mTORC1 is a central regulator of cell growth, cell proliferation, cell motility, cell survival, protein synthesis, autophagy and transcription[5]. Rapamycin has been reported to promote the apoptosis of human lens epithelial cells (LECs) and to inhibit the proliferation of rabbit LECs10–12. We estimated mTOR signalling and demonstrated the roles of autophagy and fibroblast growth factor receptor 3 (FGFR3) in aberrant apoptosis and hyperproliferation in pterygium. (Ser2448) IF staining (b-top) and p-S6 (S235/236) IHC staining (b-bottom) in pterygium and normal conjunctiva, Scale bar: 50 μm. p-mTOR positive cells (C) and p-S6 positive cells (D) were significantly increased in pterygium compared with normal conjunctiva. mTOR and mTORC1 activation were confirmed by western blotting (e and f). **p < 0.01

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