ABCA1 overexpression worsens colorectal cancer prognosis by facilitating tumour growth and caveolin-1-dependent invasiveness, and these effects can be ameliorated using the BET inhibitor apabetalone.
ABCA1 overexpression worsens colorectal cancer prognosis by facilitating tumour growth and caveolin-1-dependent invasiveness, and these effects can be ameliorated using the BET inhibitor apabetalone.
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DOI：
10.1002/1878-0261.12367
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发表时间：
2018-10
影响因子：
6.6
通讯作者：
Ramírez de Molina A
中科院分区：
文献类型：
--
作者：
Aguirre-Portolés C;Feliu J;Reglero G;Ramírez de Molina A
在诊断时，20%的结直肠癌患者存在转移。在患有原发性病变的个体中，50%的人会随着时间的推移发展为远处肿瘤。因此，早期诊断和预测侵袭性对于治疗设计和疾病预后至关重要。肿瘤细胞必须经历能量代谢的显著变化以满足细胞增殖的增加的结构和能量需求，并且代谢改变被认为是癌症的标志。在这里，我们提出了ATP结合盒转运蛋白（ABCA 1），胆固醇转运的调节剂，作为侵袭和结直肠癌生存的新标志物。ABCA 1在晚期结直肠癌患者中显著过表达，其过表达赋予增殖优势以及小窝蛋白1依赖性增加的迁移和侵袭能力。因此，ABCA 1过表达介导的细胞内胆固醇失衡可能有助于原发性肿瘤生长和向远处的扩散。此外，我们在此证明，细胞外室中载脂蛋白A1（APOA 1）（一种参与胆固醇流出和高密度脂蛋白构成的蛋白质）水平的增加通过调节考克斯-2来调节ABCA 1的表达，并补偿ABCA 1依赖的胆固醇过度输出。APOA 1通过调节细胞内胆固醇代谢而成为抑制结直肠癌转移的一种新的治疗选择。此外，我们提出了apabetalone，一种口服小分子，目前正在临床试验中评估用于治疗动脉粥样硬化，作为一种新的推定的治疗选择，以防止结直肠癌的进展，通过增加APOA 1的表达和调节胆固醇的反向转运。
At the time of diagnosis, 20% of patients with colorectal cancer present metastasis. Among individuals with primary lesions, 50% of them will develop distant tumours with time. Therefore, early diagnosis and prediction of aggressiveness is crucial for therapy design and disease prognosis. Tumoral cells must undergo significant changes in energy metabolism to meet increased structural and energetic demands for cell proliferation, and metabolic alterations are considered to be a hallmark of cancer. Here, we present the ATP‐binding cassette transporter (ABCA1), a regulator of cholesterol transport, as a new marker for invasion and colorectal cancer survival. ABCA1 is significantly overexpressed in patients at advanced stages of colorectal cancer, and its overexpression confers proliferative advantages together with caveolin‐1 dependent‐increased migratory and invasive capacities. Thus, intracellular cholesterol imbalances mediated by ABCA1 overexpression may contribute to primary tumour growth and dissemination to distant locations. Furthermore, we demonstrate here that increased levels of apolipoprotein A1 (APOA1), a protein involved in cholesterol efflux and high‐density lipoprotein constitution, in the extracellular compartment modulates expression of ABCA1 by regulating COX‐2, and compensate for ABCA1‐dependent excessive export of cholesterol. APOA1 emerges as a new therapeutic option to inhibit the promotion of colorectal cancer to metastasis by modulating intracellular cholesterol metabolism. Furthermore, we propose apabetalone, an orally available small molecule that is currently being evaluated in clinical trials for the treatment of atherosclerosis, as a new putative therapeutic option to prevent colorectal cancer progression by increasing APOA1 expression and regulating reverse transport of cholesterol.
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DOI：
10.1158/1078-0432.ccr-12-3066
发表时间：
2013-04-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Cheng Z;Gong Y;Ma Y;Lu K;Lu X;Pierce LA;Thompson RC;Muller S;Knapp S;Wang J
通讯作者：
Wang J
影响因子：
37.3
作者：
Fisher KE;Pop A;Koh W;Anthis NJ;Saunders WB;Davis GE
通讯作者：
Davis GE
影响因子：
11.2
作者：
Lee BH;Taylor MG;Robinet P;Smith JD;Schweitzer J;Sehayek E;Falzarano SM;Magi-Galluzzi C;Klein EA;Ting AH
通讯作者：
Ting AH
影响因子：
1.9
作者：
Horzum, Utku;Ozdil, Berrin;Pesen-Okvur, Devrim
通讯作者：
Pesen-Okvur, Devrim
影响因子：
28.2
作者：
Cantor JR;Sabatini DM
通讯作者：
Sabatini DM