Girdin Promotes Tumorigenesis and Chemoresistance in Lung Adenocarcinoma by Interacting with PKM2.
Girdin Promotes Tumorigenesis and Chemoresistance in Lung Adenocarcinoma by Interacting with PKM2.
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Girdin 通过与 PKM2 相互作用促进肺腺癌的肿瘤发生和化疗耐药
DOI：
10.3390/cancers14225688
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发表时间：
2022-11-19
期刊：
影响因子：
5.2
通讯作者：
Weng, Liang
中科院分区：
文献类型：
--
作者：
Cao, Fuyang;Yang, Desong;Tang, Feiyu;Lu, Can;He, Xiang;Chen, Songming;Yang, Zhanghuan;Gong, Siyuan;Sun, Lunquan;Enomoto, Atsushi;Takahashi, Masahide;Weng, Liang
有氧糖酵解是肿瘤发生和化疗耐药的关键驱动力。Girdin在癌细胞中起着至关重要的作用;然而，Girdin在有氧糖酵解中的作用仍不清楚。在这项研究中，我们首次发现，敲除Girdin显着抑制肺腺癌（LUAD）的发展在一个土生土长的LUAD小鼠模型。此外，我们发现Girdin与丙酮酸激酶M2（PKM 2）相互作用，使PKM 2活性降低，从而促进瓦尔堡效应和化疗耐药性。我们的研究结果表明，Girdin是一个潜在的治疗靶点，以克服LUAD细胞对化疗药物的耐药性。摘要Girdin是Akt的底物，在多种肿瘤中具有促肿瘤发生作用。然而，Girdin在自发性肿瘤模型中的作用尚未被探索。在这里，我们研究了Girdin在肺腺癌（LUAD）中的作用，使用本地小鼠模型，并发现Girdin导致LUAD进展和化疗耐药性通过增强瓦尔堡效应。在机制上，Girdin与丙酮酸激酶M2（PKM 2）相互作用，其在有氧糖酵解中起着至关重要的作用。此外，Girdin损害血小板衍生生长因子受体β（PDGFRβ）降解，进而促进PKM 2酪氨酸残基105（Y105）磷酸化并抑制PKM 2活性，随后促进癌细胞中的有氧糖酵解。总之，我们的研究表明，Girdin是肿瘤生长的重要调节因子，可能是克服LUAD细胞对化疗耐药性的潜在治疗靶点。
Simple Summary Aerobic glycolysis is a key driving force of tumorigenesis and chemoresistance. Girdin plays a vital role in cancer cells; however, the role of Girdin in aerobic glycolysis is still unclear. In this study, we first found that knockout of Girdin markedly inhibited lung adenocarcinoma (LUAD) progression in an autochthonous LUAD mouse model. In addition, we found that Girdin interacted with pyruvate kinase M2 (PKM2) and impaired PKM2 activity, which promoted the Warburg effect and chemoresistance. Our results suggest that Girdin is a potential therapeutic target to overcome the resistance of LUAD cells to chemotherapeutic agents. Abstract Girdin, an Akt substrate, has been reported to promote tumorigenesis in various tumors. However, the role of Girdin in a spontaneous tumor model has not yet been explored. Here, we studied the role of Girdin in lung adenocarcinoma (LUAD) using the autochthonous mouse model and found that Girdin led to LUAD progression and chemoresistance by enhancing the Warburg effect. Mechanistically, Girdin interacted with pyruvate kinase M2 (PKM2), which played a vital role in aerobic glycolysis. Furthermore, Girdin impaired Platelet Derived Growth Factor Receptor Beta (PDGFRβ) degradation, which in turn, promoted PKM2 tyrosine residue 105 (Y105) phosphorylation and inhibited PKM2 activity, subsequently promoting aerobic glycolysis in cancer cells. Taken together, our study demonstrates that Girdin is a crucial regulator of tumor growth and may be a potential therapeutic target for overcoming the resistance of LUAD cells to chemotherapy.
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DOI：
10.1016/j.omto.2020.10.003
发表时间：
2020-12-16
期刊：
Molecular therapy oncolytics
影响因子：
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作者：
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DOI：
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发表时间：
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期刊：
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期刊：
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