Keloid Disease Can Be Inhibited by Antagonizing Excessive mTOR Signaling With a Novel Dual TORC1/2 Inhibitor

Abstract

Keloid disease (KD) is a fibroproliferative lesion of unknown etiopathogenesis that possibly targets the PI3K/Akt/mTOR pathway. We investigated whether PI3K/Akt/mTOR inhibitor, Palomid 529 (P529), which targets both mammalian target of rapamycin complex 1 (mTORC-1) and mTORC-2 signaling, could exert anti-KD effects in a novel KD organ culture assay and in keloid fibroblasts (KF). Treatment of KF with P529 significantly (P < 0.05) inhibited cell spreading, attachment, proliferation, migration, and invasive properties at a low concentration (5 ng/mL) and induced substantial KF apoptosis when compared with normal dermal fibroblasts. P529 also inhibited hypoxia-inducible factor-1α expression and completely suppressed Akt, GSK3β, mTOR, eukaryotic initiation factor 4E-binding protein 1, and S6 phosphorylation. P529 significantly (P < 0.05) inhibited proliferating cell nuclear antigen and cyclin D and caused considerable apoptosis. Compared with rapamycin and wortmannin, P529 also significantly (P < 0.05) reduced keloid-associated phenotypic markers in KF. P529 caused tissue shrinkage, growth arrest, and apoptosis in keloid organ cultures and substantially inhibited angiogenesis. pS6, pAkt-Ser473, and mTOR phosphorylation were also suppressed in situ. P529 reduced cellularity and expression of collagen, fibronectin, and α-smooth muscle actin (substantially more than rapamycin). These pre-clinical in vitro and ex vivo observations are evidence that the mTOR pathway is a promising target for future KD therapy and that the dual PI3K/Akt/mTOR inhibitor P529 deserves systematic exploration as a candidate agent for the future treatment of KD.

Curcumin Suppresses Epithelial–Mesenchymal Transition of Renal Tubular Epithelial Cells through the Inhibition of Akt/mTOR Pathway

“…14, [17][18][19] Reduction in mTOR activity attenuates the progression of tubulointerstitial fibrosis in models of diabetic and polycystic kidney disease. 14,18) The evidences in carcinogenic models further suggest that increased mTOR signaling promotes loss of cadherins and increased fibrosis.…”

“…[14][15][16] It is thus evident that targeting reductions in mTOR activity attenuates the progression of tubulointerstitial fibrosis in models of diabetic and polycystic kidney disease. 14,[17][18][19] Conversely, increased mTOR signaling promotes loss of cadherins and increased fibrosis. 14,18,20) Likewise, rapamycin reduced fibrosis and attenuated disease progression in rat models of liver cirrhosis and pulmonary fibrosis.…”

WITHDRAWN: Targeting mTORC1/2 with OSI-027 inhibits proliferation and migration of keloid keratinocytes

“…It has been shown that the active form of mTOR (phospho-mTOR) is overexpressed in keloid but not in normal skin [5,7,8]. Rapamycin and other mTOR inhibitors were shown to efficiently inhibit keloid keratinocytes [5][6][7].…”

“…The active form of mTOR (phospho-mTOR) is over-expressed in keloid [6,7]. At least two multiple-protein mTOR complexes exist, including the traditional mTOR complex 1 (mTORC1), and the more recently discovered mTOR complex 2 (mTORC2) [9,10].…”

“…A set of different chemokines, cytokines and growth factors are oversecreted, which stimulate the proliferation and migration of keratinocytes (and other skin cells) to form keloid skin [1][2][3]. The hyper-activation of the serine/threonine protein kinase mammalian target of rapamycin (mTOR) plays a pivotal role in the process [4][5][6][7][8].…”