[논문]Inhibition of 3-phosphoinositide–dependent protein kinase 1 (PDK1) can revert cellular senescence in human dermal fibroblasts

An, Sugyun; Cho, Si-Young; Kang, Junsoo; Lee, Soobeom; Kim, Hyung-Su; Min, Dae-Jin; Son, EuiDong; Cho, Kwang-Hyun

doi:10.1073/pnas.1920338117

[해외논문] Inhibition of 3-phosphoinositide–dependent protein kinase 1 (PDK1) can revert cellular senescence in human dermal fibroblasts 원문보기

Proceedings of the National Academy of Sciences of the United States of America, v.117 no.49, 2020년, pp.31535 - 31546

An, Sugyun (Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology, Daejeon 34141, Republic of Korea) , Cho, Si-Young , Kang, Junsoo (R&D Unit, Amorepacific Corporation, 17074 Gyeonggi-do, Republic of Korea) , Lee, Soobeom (Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology, Daejeon 34141, Republic of Korea) , Kim, Hyung-Su , Min, Dae-Jin (Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology, Daejeon 34141, Republic of Korea) , Son, EuiDong , Cho, Kwang-Hyun (R&D Unit, Amorepacific Corporation, 17074 Gyeonggi-do, Republic of Korea)

Abstract ▼ AI-Helper

SignificanceRecent studies showed that cellular senescence, previously considered an irreversible biological phenomenon, may represent a reversible state, but the mechanism for the reversion is not well elucidated. To identify targets the inhibition of which would convert senescent cells into quiescent cells, we constructed a molecular regulatory network model of cellular senescence. From the model simulation, we identified PDK1 as a promising target that can revert the senescent state into a quiescent state. We validated this prediction in experiments with human dermal fibroblasts, which showed that PDK1 inhibition eradicates senescence hallmarks by suppressing both nuclear factor κB and mTOR signaling through the inactivation of a positive feedback loop composed of PDK1, AKT, IKBKB, and PTEN, resulting in restored skin regeneration capacity.Cellular senescence is defined as a stable, persistent arrest of cell proliferation. Here, we examine whether senescent cells can lose senescence hallmarks and reenter a reversible state of cell-cycle arrest (quiescence). We constructed a molecular regulatory network of cellular senescence based on previous experimental evidence. To infer the regulatory logic of the network, we performed phosphoprotein array experiments with normal human dermal fibroblasts and used the data to optimize the regulatory relationships between molecules with an evolutionary algorithm. From ensemble analysis of network models, we identified 3-phosphoinositide–dependent protein kinase 1 (PDK1) as a promising target for inhibitors to convert the senescent state to the quiescent state. We showed that inhibition of PDK1 in senescent human dermal fibroblasts eradicates senescence hallmarks and restores entry into the cell cycle by suppressing both nuclear factor κB and mTOR signaling, resulting in restored skin regeneration capacity. Our findings provide insight into a potential therapeutic strategy to treat age-related diseases associated with the accumulation of senescent cells.

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