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NVP-BKM120通过FoxO3a依赖的PUMA诱导抑制结肠癌生长。

NVP-BKM120 inhibits colon cancer growth via FoxO3a-dependent PUMA induction.

作者信息

Yang Shida, Li Xin, Guan Wenchang, Qian Mingqin, Yao Zhicheng, Yin Xiaoxue, Zhao Hongmei

机构信息

Department of Laboratory Medicine, The People's Hospital of Liaoning Province, Shenyang, China.

Department of Anesthesia, The People's Hospital of Liaoning Province, Shenyang, China.

出版信息

Oncotarget. 2017 Sep 15;8(47):83052-83062. doi: 10.18632/oncotarget.20943. eCollection 2017 Oct 10.

DOI:10.18632/oncotarget.20943
PMID:29137323
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5669949/
Abstract

NVP-BKM120, a potent and highly selective PI3K inhibitor, is currently being investigated in phase I/II clinical trials. The mechanisms of action of NVP-BKM120 in colon cancer cells are unclear. In the present study, we investigated how NVP-BKM120 suppresses colon cancer cells growth and potentiates effects of other chemotherapeutic drugs. We found that NVP-BKM120 treatment enhance PUMA induction irrespective of p53 status through the FoxO3a pathway following AKT inhibition. Furthermore, PUMA is required for NVP-BKM120-induced apoptosis in colon cancer cells. In addition, NVP-BKM120 also synergized with 5-Fluorouracil or regorafenib to induce marked apoptosis via PUMA induction. Deficiency of PUMA suppressed apoptosis and antitumor effect of NVP-BKM120 in xenograft model. These results demonstrate a key role of PUMA in mediating the anticancer effects of NVP-BKM120 and suggest that PUMA could be used as an indicator of NVP-BKM120 sensitivity, and also have important implications for it clinical applications.

摘要

NVP-BKM120是一种强效且高度选择性的PI3K抑制剂，目前正处于I/II期临床试验阶段。NVP-BKM120在结肠癌细胞中的作用机制尚不清楚。在本研究中，我们探究了NVP-BKM120如何抑制结肠癌细胞生长并增强其他化疗药物的效果。我们发现，在抑制AKT后，NVP-BKM120处理可通过FoxO3a途径增强PUMA的诱导，而与p53状态无关。此外，PUMA是NVP-BKM120诱导结肠癌细胞凋亡所必需的。此外，NVP-BKM120还与5-氟尿嘧啶或瑞戈非尼协同作用，通过诱导PUMA来显著诱导凋亡。在异种移植模型中，PUMA的缺失抑制了NVP-BKM120的凋亡和抗肿瘤作用。这些结果证明了PUMA在介导NVP-BKM120抗癌作用中的关键作用，并表明PUMA可作为NVP-BKM120敏感性的指标，对其临床应用也具有重要意义。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5101/5669949/a3ea398d4bfe/oncotarget-08-83052-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5101/5669949/b2f907fee7a3/oncotarget-08-83052-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5101/5669949/db61cd311938/oncotarget-08-83052-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5101/5669949/3a257669135b/oncotarget-08-83052-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5101/5669949/496736ef6f23/oncotarget-08-83052-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5101/5669949/501e75f9b6cc/oncotarget-08-83052-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5101/5669949/a3ea398d4bfe/oncotarget-08-83052-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5101/5669949/b2f907fee7a3/oncotarget-08-83052-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5101/5669949/db61cd311938/oncotarget-08-83052-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5101/5669949/3a257669135b/oncotarget-08-83052-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5101/5669949/496736ef6f23/oncotarget-08-83052-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5101/5669949/501e75f9b6cc/oncotarget-08-83052-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5101/5669949/a3ea398d4bfe/oncotarget-08-83052-g006.jpg

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Mcl-1 Degradation Is Required for Targeted Therapeutics to Eradicate Colon Cancer Cells.Mcl-1降解是靶向治疗根除结肠癌细胞所必需的。
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Idelalisib induces PUMA-dependent apoptosis in colon cancer cells.
AP-2α Regulates S-Phase and Is a Marker for Sensitivity to PI3K Inhibitor Buparlisib in Colon Cancer.
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PI3K Abrogation Using Pan-PI3K Inhibitor BKM120 Gives Rise to a Significant Anticancer Effect on AML-Derived KG-1 Cells by Inducing Apoptosis and G2/M Arrest.使用泛 PI3K 抑制剂 BKM120 阻断 PI3K 可通过诱导细胞凋亡和 G2/M 期阻滞对 AML 衍生的 KG-1 细胞产生显著的抗癌作用。
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