Abstract
// Jun Chen 1, * , Ke Liu 1, * , Yang Liu 1 , Xue Wang 1 and Zhen Zhang 1 1 Department of Dermatology and Dermatologic Surgery, Shanghai Ninth People’s Hospital, Affiliated to Shanghai Jiaotong University School of Medicine, Center for Specialty Strategy Research of Shanghai JiaoTong University China Hospital Development Institute, Shanghai 200011, China * These authors contributed equally to this work Correspondence to: Zhen Zhang, email: zz6503@126.com Keywords: keloid keratinocytes; cell migration; mTOR; OSI-027; signaling Received: August 08, 2017 Accepted: December 11, 2017 Published: January 02, 2018 ABSTRACT Keloid is a dermal proliferative disorder characterized by the excessive keratinocyte proliferation and migration. mTOR over-activation is involved in the process. Here, we show that both mTOR complex 1 (mTORC1) and mTORC2 were hyper-activated in keloid-derived primary keratinocytes. OSI-027, an mTOR kinase inhibitor, potently inhibited proliferation and migration of keloid keratinocytes. OSI-027 disrupted the assembly of mTORC1 (mTOR-Raptor) and mTORC2 (mTOR-Rictor-mLST8). Further, OSI-027 completely blocked the phosphorylations of the mTORC1 substrates (S6K1, S6 and 4EBP1) and the mTORC2 substrate (AKT, at Ser-473). OSI-027 was potent than rapamycin in inhibiting keloid keratinocytes. Moreover, restoring mTORC1 activation by the introduction of the constitutively active S6K1 only partly alleviated OSI-027-induced suppression on keloid keratinocytes. Notably, mTOR2 inhibition by Rictor siRNA also inhibited keloid keratinocyte proliferation and migration, although less efficiently than OSI-027. Together, concurrent targeting of mTORC1/2 by OSI-027 potently inhibits keloid keratinocyte proliferation and migration.
Highlights
Keloid is characterized by the formation of exuberant and autonomous scar tissue that extends the clinical border of the original wound [1,2,3]
We show that both mammalian target of rapamycin (mTOR) complex 1 and mTOR complex 2 (mTORC2) were hyper-activated in keloid-derived primary keratinocytes
In keloid keratinocytes, BrdU (Figure 1C) and [H3] DNA incorporation (Figure 1D) were both increased. These results demonstrate the increased cell proliferation of keloid primary keratinocytes compared to normal keratinocytes (Figure 1A–1D)
Summary
Keloid is characterized by the formation of exuberant and autonomous scar tissue that extends the clinical border of the original wound [1,2,3]. It often forms as a result of dermal injuries, and is considered, to a limited extent, as a benign tumor [1,2,3]. 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]. At least two multiple-protein mTOR complexes exist, including the traditional mTOR complex 1
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