Ren Hui, Guo Hua, Thakur Asmitananda, Zhang Shuo, Wang Ting, Liang Yiqian, Shi Puyu, Gao Lei, Liu Feng, Feng Jing, Chen Tianjun, Yang Tian, Shang Dong, Liu Johnson J, Xu Feng, Chen Mingwei
Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China.
Bioinspired Engineering and Biomechanics Center, Xi'an Jiaotong University, Xi'an, Shaanxi, China.
Oncotarget. 2016 Oct 11;7(41):67277-67287. doi: 10.18632/oncotarget.11645.
NVP-BKM120 (BKM120) is a new pan-class I phosphatidylinositol-3 kinase (PI3K) inhibitor and has been tested in clinical trials as an anticancer agent. In this study, we determined whether BKM120 induces autophagy and the impact of autophagy induction on BKM120's growth-inhibitory activity. BKM120 potently induced elevation of autophagosome-bound type II LC3 (LC3-II) protein, predominantly in cell lines insensitive to BKM120, thereby inducing autophagy. The presence of lysosomal protease inhibitor chloroquine further enhanced the levels of LC3-II. BKM120 combined with chloroquine, enhanced growth-inhibitory effects including induction of apoptosis, suggesting that autophagy is a protective mechanism counteracting BKM120's growth-inhibitory activity. Interestingly, BKM120 increased p-ERK1/2 levels. When blocking the activation of this signaling with MEK inhibitors or with knockdown of ERK1/2, the ability of BKM120 to increase LC3-II was attenuated and the growth-inhibitory effects including induction of apoptosis were accordingly enhanced, suggesting that the MEK/ERK activation contributes to BKM120-induced authophagy. In mouse xenograft model, we also found that the combination of BKM120 and PD0325901 synergistically suppressed cell growth in human lung cancer cells. Thus, the current study not only reveals mechanisms accounting for BKM120-induced autophagy, but also suggests an alternative method to enhance BKM120's therapeutic efficacy against non-small cell lung cancer(NSCLC) by blocking autophagy with either a lysosomal protease inhibitor or MEK inhibitor.
NVP-BKM120（BKM120）是一种新型的泛I类磷脂酰肌醇-3激酶（PI3K）抑制剂，已作为抗癌药物进行临床试验。在本研究中，我们确定了BKM120是否诱导自噬以及自噬诱导对BKM120生长抑制活性的影响。BKM120主要在对BKM120不敏感的细胞系中强力诱导自噬体结合型II LC3（LC3-II）蛋白升高，从而诱导自噬。溶酶体蛋白酶抑制剂氯喹的存在进一步提高了LC3-II的水平。BKM120与氯喹联合使用可增强包括诱导凋亡在内的生长抑制作用，表明自噬是对抗BKM120生长抑制活性的一种保护机制。有趣的是，BKM120增加了p-ERK1/2水平。当用MEK抑制剂或通过敲低ERK1/2阻断该信号通路的激活时，BKM120增加LC3-II的能力减弱，包括诱导凋亡在内的生长抑制作用相应增强，表明MEK/ERK激活促进了BKM120诱导的自噬。在小鼠异种移植模型中，我们还发现BKM120与PD0325901联合使用可协同抑制人肺癌细胞的生长。因此，本研究不仅揭示了BKM120诱导自噬的机制，还提出了一种通过用溶酶体蛋白酶抑制剂或MEK抑制剂阻断自噬来提高BKM120对非小细胞肺癌（NSCLC）治疗效果的替代方法。
