Browsing by Author "Huang, De"

Now showing 1 - 4 of 4
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    Antagonizing the irreversible thrombomodulin-initiated proteolytic signaling alleviates age-related liver fibrosis via senescent cell killing.
    (Cell research, 2023-07) Pan, Christopher C; Maeso-Díaz, Raquel; Lewis, Tylor R; Xiang, Kun; Tan, Lianmei; Liang, Yaosi; Wang, Liuyang; Yang, Fengrui; Yin, Tao; Wang, Calvin; Du, Kuo; Huang, De; Oh, Seh Hoon; Wang, Ergang; Lim, Bryan Jian Wei; Chong, Mengyang; Alexander, Peter B; Yao, Xuebiao; Arshavsky, Vadim Y; Li, Qi-Jing; Diehl, Anna Mae; Wang, Xiao-Fan
    Cellular senescence is a stress-induced, stable cell cycle arrest phenotype which generates a pro-inflammatory microenvironment, leading to chronic inflammation and age-associated diseases. Determining the fundamental molecular pathways driving senescence instead of apoptosis could enable the identification of senolytic agents to restore tissue homeostasis. Here, we identify thrombomodulin (THBD) signaling as a key molecular determinant of the senescent cell fate. Although normally restricted to endothelial cells, THBD is rapidly upregulated and maintained throughout all phases of the senescence program in aged mammalian tissues and in senescent cell models. Mechanistically, THBD activates a proteolytic feed-forward signaling pathway by stabilizing a multi-protein complex in early endosomes, thus forming a molecular basis for the irreversibility of the senescence program and ensuring senescent cell viability. Therapeutically, THBD signaling depletion or inhibition using vorapaxar, an FDA-approved drug, effectively ablates senescent cells and restores tissue homeostasis in liver fibrosis models. Collectively, these results uncover proteolytic THBD signaling as a conserved pro-survival pathway essential for senescent cell viability, thus providing a pharmacologically exploitable senolytic target for senescence-associated diseases.
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    Branched-Chain Amino Acid Accumulation Fuels the Senescence-Associated Secretory Phenotype.
    (Advanced science (Weinheim, Baden-Wurttemberg, Germany), 2023-11) Liang, Yaosi; Pan, Christopher; Yin, Tao; Wang, Lu; Gao, Xia; Wang, Ergang; Quang, Holly; Huang, De; Tan, Lianmei; Xiang, Kun; Wang, Yu; Alexander, Peter B; Li, Qi-Jing; Yao, Tso-Pang; Zhang, Zhao; Wang, Xiao-Fan
    The essential branched-chain amino acids (BCAAs) leucine, isoleucine, and valine play critical roles in protein synthesis and energy metabolism. Despite their widespread use as nutritional supplements, BCAAs' full effects on mammalian physiology remain uncertain due to the complexities of BCAA metabolic regulation. Here a novel mechanism linking intrinsic alterations in BCAA metabolism is identified to cellular senescence and the senescence-associated secretory phenotype (SASP), both of which contribute to organismal aging and inflammation-related diseases. Altered BCAA metabolism driving the SASP is mediated by robust activation of the BCAA transporters Solute Carrier Family 6 Members 14 and 15 as well as downregulation of the catabolic enzyme BCAA transaminase 1 during onset of cellular senescence, leading to highly elevated intracellular BCAA levels in senescent cells. This, in turn, activates the mammalian target of rapamycin complex 1 (mTORC1) to establish the full SASP program. Transgenic Drosophila models further indicate that orthologous BCAA regulators are involved in the induction of cellular senescence and age-related phenotypes in flies, suggesting evolutionary conservation of this metabolic pathway during aging. Finally, experimentally blocking BCAA accumulation attenuates the inflammatory response in a mouse senescence model, highlighting the therapeutic potential of modulating BCAA metabolism for the treatment of age-related and inflammatory diseases.
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    Cancer-cell-derived GABA promotes β-catenin-mediated tumour growth and immunosuppression.
    (Nature cell biology, 2022-02) Huang, De; Wang, Yan; Thompson, J Will; Yin, Tao; Alexander, Peter B; Qin, Diyuan; Mudgal, Poorva; Wu, Haiyang; Liang, Yaosi; Tan, Lianmei; Pan, Christopher; Yuan, Lifeng; Wan, Ying; Li, Qi-Jing; Wang, Xiao-Fan
    Many cancers have an unusual dependence on glutamine. However, most previous studies have focused on the contribution of glutamine to metabolic building blocks and the energy supply. Here, we report that cancer cells with aberrant expression of glutamate decarboxylase 1 (GAD1) rewire glutamine metabolism for the synthesis of γ-aminobutyric acid (GABA)-a prominent neurotransmitter-in non-nervous tissues. An analysis of clinical samples reveals that increased GABA levels predict poor prognosis. Mechanistically, we identify a cancer-intrinsic pathway through which GABA activates the GABAB receptor to inhibit GSK-3β activity, leading to enhanced β-catenin signalling. This GABA-mediated β-catenin activation both stimulates tumour cell proliferation and suppresses CD8+ T cell intratumoural infiltration, such that targeting GAD1 or GABABR in mouse models overcomes resistance to anti-PD-1 immune checkpoint blockade therapy. Our findings uncover a signalling role for tumour-derived GABA beyond its classic function as a neurotransmitter that can be targeted pharmacologically to reverse immunosuppression.
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    Synthetic lethality between HER2 and transaldolase in intrinsically resistant HER2-positive breast cancers.
    (Nature communications, 2018-10) Ding, Yi; Gong, Chang; Huang, De; Chen, Rui; Sui, Pinpin; Lin, Kevin H; Liang, Gehao; Yuan, Lifeng; Xiang, Handan; Chen, Junying; Yin, Tao; Alexander, Peter B; Wang, Qian-Fei; Song, Er-Wei; Li, Qi-Jing; Wood, Kris C; Wang, Xiao-Fan
    Intrinsic resistance to anti-HER2 therapy in breast cancer remains an obstacle in the clinic, limiting its efficacy. However, the biological basis for intrinsic resistance is poorly understood. Here we performed a CRISPR/Cas9-mediated loss-of-function genetic profiling and identified TALDO1, which encodes the rate-limiting transaldolase (TA) enzyme in the non-oxidative pentose phosphate pathway, as essential for cellular survival following pharmacological HER2 blockade. Suppression of TA increases cell susceptibility to HER2 inhibition in two intrinsically resistant breast cancer cell lines with HER2 amplification. Mechanistically, TA depletion combined with HER2 inhibition significantly reduces cellular NADPH levels, resulting in excessive ROS production and deficient lipid and nucleotide synthesis. Importantly, higher TA expression correlates with poor response to HER2 inhibition in a breast cancer patient cohort. Together, these results pinpoint TA as a novel metabolic enzyme possessing synthetic lethality with HER2 inhibition that can potentially be exploited as a biomarker or target for combination therapy.