Abstract:
:Keloid is a dermal proliferative disorder characterized by the excessive proliferation and migration of keratinocytes and fibroblasts. Over-activation of the serine/threonine protein kinase, mammalian target of rapamycin (mTOR), plays a pivotal role in the process. Here, we show that both mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2) were hyper-activated in keloid-derived primary keratinocytes. Further, OSI-027, an mTOR kinase inhibitor, potently inhibited proliferation and migration of keloid keratinocytes. At the molecular level, OSI-027 disrupted the assembly of mTORC1 (mTOR-Raptor) and mTORC2 (mTOR-Rictor-mLST8). Further, OSI-027 almost completely blocked the phosphorylation of the mTORC1 substrates, S6K1, S6 and 4EBP1, and the mTORC2 substrate, AKT, at Ser-473. The OSI-027 treatment of keloid keratinocytes showed more effectively inhibited cell proliferation and migration compared to the mTORC1 inhibitor, rapamycin. Moreover, restoring mTORC1 activation by the introduction of the constitutively active S6K1 only partly alleviated OSI-027-induced inhibition of keloid keratinocytes. Notably, mTOR2 inhibition by Rictor siRNAs also inhibited keloid keratinocyte proliferation and migration, but less efficiently than OSI-027. Together, our results imply that concurrent targeting of mTORC1/2 by OSI-027 potently inhibits the proliferation and the migration of keloid keratinocytes. Thus, OSI-027 may have translational value for the treatment of keloid.
journal_name
Exp Dermatoljournal_title
Experimental dermatologyauthors
Chen J,Liu K,Liu Y,Wang X,Zhang Zdoi
10.1111/exd.13882subject
Has Abstractpub_date
2019-03-01 00:00:00pages
270-275issue
3eissn
0906-6705issn
1600-0625journal_volume
28pub_type
杂志文章abstract::In the 1970s, studies of tissue architecture and cell proliferation were used to formulate a new model of epidermal homeostasis. This asserted that the tissue was maintained by long-lived, slow-cycling, self-renewing stem cells that generate a short-lived population of transit amplifying (TA) cells, which undergo term...
journal_title:Experimental dermatology
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journal_title:Experimental dermatology
pub_type: 杂志文章
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journal_title:Experimental dermatology
pub_type: 杂志文章
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journal_title:Experimental dermatology
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