生物科技研究所林愷悌副教授Associate Professor Kai-Ti Lin, Institute of Biotechnology
生命科學暨醫學院教師傑出研究介紹
Introduction to Outstanding Research by Faculty Members of the College of Life Sciences and Medicine
生物科技研究所 林愷悌副教授
Associate Professor Kai-Ti Lin, Institute of Biotechnology
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清大生醫學院生技所林愷悌副教授（右二）與研究團隊成員 Associate Professor Dr. Kai-Ti Lin of the Institute of Biotechnology, College of Life Sciences and Medicine, National Tsing Hua University, with research team member. |
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Hydrogen sulfide coordinates glucose metabolism switch through destabilizing tetrameric pyruvate kinase M2 |
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自然通訊Nature Communications |
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主持人Principle Investigator： 林愷悌 副教授Kai-Ti Lin, Associate Professor 國立清華大學生命科學暨醫學院 生物科技研究所 Institute of Biotechnology (IBT), College of Life Science and Medicine (CLSM), National Tsing Hua University (NTHU). 參與者Participants:： 鄭惠春 副教授 國立清華大學生命科學暨醫學院 生物資訊與結構生物研究所 Hui-Chun Cheng, Associate Professor. Institute of Bioinformatics and Structural Biology, CLSM, NTHU 王陸海 院士 中國醫藥大學 Lu-Hai Wang, CMU 龔行健院士 台北醫學大學 Hsing-Jien Kung, TMU 王雯靜 教授 國立清華大學生命科學暨醫學院 分子與細胞生物研究所 Wen-Ching Wang, Professor, Institute of Molecular and Cellular Biology, NTHU 王慧菁 教授 國立清華大學生命科學暨醫學院 分子與細胞生物研究所 Lily Hui-Ching Wang, Professor, Institute of Molecular and Cellular Biology, NTHU 林淑宜 教授 國家衛生研究院 Shu-Yi Lin, Professor, National Health and Research Institutes (NHRI) |
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摘要 Abstract |
為了滿足快速增殖的需求，癌細胞常將能量代謝路徑由呼吸作用轉換為合成作用，以此將葡萄糖代謝產物用於DNA合成，促進細胞分裂與腫瘤生長。在此過程中，調控PKM2活性下降，有助於癌細胞儲存糖解作用的中間產物，並將其導入各種生合成路徑，進一步推動腫瘤的生長。本研究欲探討硫化氫（H₂S）是否能透過硫化後修飾（sulfhydration）調節PKM2活性，進而改變癌細胞的糖代謝途徑，促進其分裂與腫瘤增生。在本計畫中，我們深入探討硫化氫於癌症代謝中的功能角色，期望藉此尋找可針對癌細胞特有代謝路徑的治療策略，並結合基因體學、蛋白質體學及代謝體學等技術，為患者量身打造新型的個人化治療方案，進一步提升癌症治療成功率與病友生活品質。 Most cancer cells shift their energy metabolism from respiration to anabolic pathways, redirecting glucose metabolites toward DNA synthesis to meet the demands of rapid proliferation. In this process, the downregulation of PKM2 activity facilitates the accumulation of glycolytic intermediates, which are then channeled into anabolic processes to support tumor growth. This study aims to investigate whether hydrogen sulfide (H₂S) can modulate PKM2 activity through sulfhydration, thereby altering glucose metabolism in cancer cells to favor pathways that promote cell division and tumor progression. We plan to elucidate the role of H₂S in cancer metabolism and explore potential therapeutic strategies that target cancer-specific metabolic pathways. By integrating genomics, proteomics, and metabolomics approaches, we hope to develop personalized treatment options, ultimately improving the success rates of cancer therapies and enhancing patients’ quality of life. |
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研究成果Result/Contributions |
本研究探討硫化氫透過蛋白質轉譯後修飾，調控癌細胞葡萄糖代謝之機制。我們的研究結果顯示，H₂S可透過硫化後修飾修飾PKM2蛋白中的半胱胺酸，尤其是C326這個位點，進而使PKM2四聚體結構解離為單體及二聚體，導致其酵素活性下降，並增強其轉錄調控功能以促進腫瘤生長。我們進一步將PKM2的C326位點突變為絲胺酸（C326S）後，可阻斷H₂S對PKM2的硫化後修飾，使PKM2維持穩定四聚體結構，並經結晶結構分析證實此結果。而在癌細胞中表現PKM2-C326S突變株後，葡萄糖代謝途徑會由有氧糖解作用重新導向粒線體呼吸作用，顯著抑制腫瘤生長，無論在體外細胞模式或體內腫瘤動物模型皆獲得一致結果。綜合而言，本研究揭示H₂S透過對PKM2進行硫化後修飾促進癌症葡萄糖代謝重組並促使腫瘤快速生長的新穎機制，並提出阻斷PKM2硫化後修飾為潛力的癌症代謝治療策略，提供未來精準治療之新方向。 In this study, we investigated the role of H₂S in modulating glucose metabolism in cancer cells through post-translational modification of PKM2. Our results demonstrate that H₂S destabilizes the active PKM2 tetramer, converting it into monomeric and dimeric forms through sulfhydration at Cysteine 326. This modification leads to reduced PKM2 enzymatic activity while enhancing its non-metabolic, transcriptional regulatory functions that contribute to tumor progression. Importantly, we found that blocking PKM2 sulfhydration at C326 via amino acid substitution (C326S) stabilizes the PKM2 tetramer, as confirmed by structural analysis, and prevents the H₂S-induced shift in glucose metabolism. Cancer cells expressing the PKM2-C326S mutant exhibited a metabolic shift from aerobic glycolysis back to mitochondrial respiration, resulting in significantly suppressed tumor growth both in vitro and in vivo. These findings reveal a novel mechanism by which H₂S promotes tumorigenesis through the sulfhydration-dependent inactivation of PKM2. Furthermore, our study highlights the therapeutic potential of targeting PKM2 sulfhydration as a strategy to disrupt cancer-specific metabolic reprogramming. |
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其他參考資料 Related Information |
首頁故事 https://www.nthu.edu.tw/hotNews/content/1198 清華臉書 https://www.instagram.com/p/DDGqGMxSyMV/?img_index=1 https://www.threads.net/@nthu_official/post/DDGqhTtSbWA 中央社 https://www.cna.com.tw/news/aloc/202412030071.aspx https://udn.com/news/story/7266/8400059 https://health.ltn.com.tw/article/breakingnews/4882222 https://www.chinatimes.com/realtimenews/20241203003547-260405?chdtv ETtoday新聞 https://www.ettoday.net/news/20241203/2866437.htm 台視新聞 https://news.ttv.com.tw/news/11312030035800N/amp https://news.tvbs.com.tw/life/2706934 非凡新聞 https://news.ustv.com.tw/newsdetail/20241203A001029 https://www.setn.com/News.aspx?NewsID=1573311 https://technews.tw/2024/12/03/nature/ 太報 https://www.taisounds.com/news/content/92/160749 |
