Positive regulation of PFKFB3 by PIM2 promotes glycolysis and paclitaxel resistance in breast cancer.
Positive regulation of PFKFB3 by PIM2 promotes glycolysis and paclitaxel resistance in breast cancer.
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DOI：
10.1002/ctm2.400
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发表时间：
2021-04
影响因子：
10.6
通讯作者：
Yu Z
中科院分区：
文献类型：
--
作者：
Lu C;Qiao P;Sun Y;Ren C;Yu Z
乳腺癌是世界上最常见的女性恶性肿瘤之一。化疗耐药是BC治疗失败的主要原因，导致肿瘤复发和转移。研究表明糖酵解与BC进展和耐药性之间存在密切关系。关键的糖酵解调节剂PFKFB 3在BC进展和耐药性过程中发挥作用。然而，其机制仍然未知。通过质谱分析发现PIM 2是PFKFB 3潜在的新结合蛋白。免疫共沉淀和蛋白质印迹用于验证BC中PIM 2和PFKFB 3之间的相互作用以及PIM 2磷酸化PFKFB 3调节蛋白质功能的分子机制。PFKFB 3突变形式用于证明在BC耐药性中需要PFKFB 3。我们鉴定了PIM 2是PFKFB 3的一个新的结合蛋白。我们使用生物化学方法确定PIM 2可以直接结合并改变PFKFB 3在Ser 478的磷酸化，以通过泛素-蛋白酶体途径增强PFKFB 3蛋白的稳定性。重要的是，PFKFB 3在Ser 478处的磷酸化促进了糖酵解、BC细胞生长和紫杉醇耐药性以及PIM 2在体外和体内的作用。我们的研究表明，PIM 2介导PFKFB 3磷酸化，从而调节糖酵解和紫杉醇耐药性，以促进BC中的肿瘤进展，并为靶向PFKFB 3作为BC治疗中对抗紫杉醇耐药性的新策略提供临床前证据。我们证明，PIM 2介导PFKFB 3磷酸化，从而调节糖酵解和紫杉醇耐药，以促进乳腺癌的肿瘤进展，并提供临床前证据，靶向PFKFB 3作为乳腺癌治疗的新策略，以对抗紫杉醇耐药。
Breast cancer (BC) is one of the most common female malignancies in the world. Chemotherapeutic resistance is the major cause of BC therapy failure, leading to tumor recurrence and metastasis. Studies have illustrated the close relationship between glycolysis and BC progression and drug resistance. The key glycolysis regulator, PFKFB3 makes a difference during BC progression and drug resistance. However, the mechanism remains to be unknown. Mass spectrometry analyses were used to found that PIM2 was a potential new binding protein of PFKFB3. Co‐immunoprecipitated and western blot were used to verify the interaction between PIM2 and PFKFB3 in BC and the molecular mechanism by which PIM2 phosphorylates PFKFB3 in regulating the protein function. PFKFB3 mutant forms were used to demonstrate the need for PFKFB3 in BC drug resistance. We identified that PIM2 is a new binding protein of PFKFB3. We used biochemical methods to determine that PIM2 can directly bind and change the phosphorylation of PFKFB3 at Ser478 to enhance PFKFB3 protein stability through the ubiquitin‐proteasome pathway. Importantly, phosphorylation of PFKFB3 at Ser478 promoted glycolysis, BC cell growth, and paclitaxel resistance together with PIM2 in vitro and in vivo. Our study demonstrates that PIM2 mediates PFKFB3 phosphorylation thus regulates glycolysis and paclitaxel resistance to promote tumor progression in BC and provides preclinical evidence for targeting PFKFB3 as a new strategy in BC treatment to battle paclitaxel resistance. We demonstrates that PIM2 mediates PFKFB3 phosphorylation thus regulates glycolysis and paclitaxel resistance to promote tumor progression in breast cancer, and provides preclinical evidence for targeting PFKFB3 as a new strategy in breast cancer treatment to battle paclitaxel resistance.
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影响因子：
13.8
作者：
Liberti MV;Locasale JW
通讯作者：
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影响因子：
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作者：
Ren C;Yang T;Qiao P;Wang L;Han X;Lv S;Sun Y;Liu Z;Du Y;Yu Z
通讯作者：
Yu Z
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20.3
作者：
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Garcia, Pablo D.
影响因子：
28.5
作者：
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通讯作者：
Dai, Zhijun
DOI：
10.1016/j.bbacli.2015.03.003
发表时间：
2015-06
期刊：
BBA clinical
影响因子：
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作者：
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通讯作者：
McCann A