Co-targeting hexokinase 2-mediated Warburg effect and ULK1-dependent autophagy suppresses tumor growth of PTEN- and TP53-deficiency-driven castration-resistant prostate cancer.
Co-targeting hexokinase 2-mediated Warburg effect and ULK1-dependent autophagy suppresses tumor growth of PTEN- and TP53-deficiency-driven castration-resistant prostate cancer.
复制标题
共同靶向己糖酶2介导的WARBURG效应和ULK1依赖性自噬抑制了PTEN-和TP53缺陷驱动的耐Cantration抗性前列腺癌的肿瘤生长。
DOI：
10.1016/j.ebiom.2016.03.022
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发表时间：
2016-05
期刊：
影响因子：
11.1
通讯作者：
Deng Y
中科院分区：
文献类型：
--
作者：
Wang L;Wang J;Xiong H;Wu F;Lan T;Zhang Y;Guo X;Wang H;Saleem M;Jiang C;Lu J;Deng Y
目前，对第二代抗雄激素受体（AR）轴治疗产生耐药性的去势抵抗性前列腺癌（CRPC）患者没有治疗选择。在这里，我们报告了在鼠前列腺上皮中Pten和p53的共缺失，通常在人CRPC中观察到，导致AR非依赖性CRPC，从而在多个独立但互补的临床前小鼠模型中赋予对第二代雄激素剥夺疗法（ADT）的从头抗性。相比之下，机制驱动的共靶向己糖激酶2（HK 2）介导的瓦尔堡效应与2-脱氧葡萄糖（2-DG）和ULK 1依赖性自噬与氯喹（CQ）通过内源性凋亡选择性杀死癌细胞，导致异种移植物中的肿瘤消退，导致几乎完全的肿瘤抑制，并显着延长Pten −/p53缺陷驱动的CRPC小鼠模型的生存期。机制上，2-DG引起AMPK磷酸化，其进而抑制mTORC 1-S6 K1翻译信号传导以优先阻断抗凋亡蛋白MCL-1合成以引发细胞凋亡依赖性凋亡，同时激活ULK 1驱动的自噬以使细胞存活以抵消抗Warburg效应的凋亡作用。因此，用CQ抑制自噬使癌细胞在2-DG攻击时对凋亡敏感。考虑到2-DG被推荐用于前列腺癌的II期临床试验，并且CQ已在临床上用作抗疟疾药物数十年，我们体内原理验证研究的临床前结果可立即转化为临床试验，以评估通过组合方式对目前无法治愈的携带PTEN和TP 53突变的CRPC子集的治疗功效。PTEN/TP 53缺失驱动HK 2依赖性前列腺肿瘤生长绕过抗AR轴治疗靶向HK 2介导的瓦尔堡效应激活AMPK-ULK 1依赖性自噬以维持细胞存活靶向HK 2介导的瓦尔堡效应调节AMPK-mTORC 1-S6 K1翻译信号传导以减少MCL-1以促进细胞凋亡共靶向瓦尔堡效应和自噬抑制Pten-/p53缺陷型前列腺癌模型中的肿瘤生长
Currently, no therapeutic options exist for castration-resistant prostate cancer (CRPC) patients who have developed resistance to the second generation anti-androgen receptor (AR) axis therapy. Here we report that co-deletion of Pten and p53 in murine prostate epithelium, often observed in human CRPC, leads to AR-independent CRPC and thus confers de novo resistance to second generation androgen deprivation therapy (ADT) in multiple independent yet complementary preclinical mouse models. In contrast, mechanism-driven co-targeting hexokinase 2 (HK2)-mediated Warburg effect with 2-deoxyglucose (2-DG) and ULK1-dependent autophagy with chloroquine (CQ) selectively kills cancer cells through intrinsic apoptosis to cause tumor regression in xenograft, leads to a near-complete tumor suppression and remarkably extends survival in Pten −/p53-deficiency-driven CRPC mouse model. Mechanistically, 2-DG causes AMPK phosphorylation, which in turn inhibits mTORC1-S6K1 translation signaling to preferentially block anti-apoptotic protein MCL-l synthesis to prime mitochondria-dependent apoptosis while simultaneously activates ULK1-driven autophagy for cell survival to counteract the apoptotic action of anti-Warburg effect. Accordingly, inhibition of autophagy with CQ sensitizes cancer cells to apoptosis upon 2-DG challenge. Given that 2-DG is recommended for phase II clinical trials for prostate cancer and CQ has been clinically used as an anti-malaria drug for many decades, the preclinical results from our proof-of-principle studies in vivo are imminently translatable to clinical trials to evaluate the therapeutic efficacy by the combination modality for a subset of currently incurable CRPC harboring PTEN and TP53 mutations. PTEN/TP53 loss drives HK2-dependent prostate tumor growth bypassing anti-AR axis therapy Targeting HK2-mediated Warburg effect activates AMPK-ULK1-dependent autophagy for cell survival Targeting HK2-mediated Warburg effect regulates AMPK-mTORC1-S6K1 translation signaling to reduce MCL-1 for cell apoptosis Co-targeting Warburg effect and autophagy suppresses tumor growth in Pten-/p53-deficient prostate cancer models