Molecular subtype-specific responses of colon cancer cells to the SMAC mimetic Birinapant.
Molecular subtype-specific responses of colon cancer cells to the SMAC mimetic Birinapant.
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DOI：
10.1038/s41419-020-03232-z
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发表时间：
2020-11-30
影响因子：
9
通讯作者：
Prehn JHM
中科院分区：
文献类型：
--
作者：
Fichtner M;Bozkurt E;Salvucci M;McCann C;McAllister KA;Halang L;Düssmann H;Kinsella S;Crawford N;Sessler T;Longley DB;Prehn JHM
结直肠癌是一种分子异质性疾病。在辅助或姑息治疗中，对基因毒性化疗的反应在患者之间差异很大，并且结直肠癌细胞通常通过逃避凋亡来抵抗化疗。凋亡蛋白抑制剂（IAP）的拮抗剂可以通过降解cIAP 1和cIAP 2蛋白以及通过抑制XIAP来恢复缺陷的凋亡信号传导。由于这些靶点的多种分子作用机制，对IAP拮抗剂的反应在分子上不同的结肠癌细胞之间可能不同。在这项研究中，在14种结肠癌细胞系中研究了对IAP拮抗剂Birinapant和奥沙利铂/5-氟尿嘧啶（5-FU）的反应，这些细胞系代表了共识分子亚型（CMS）。单独用Birinapant处理不会导致该细胞系组中凋亡细胞的显著增加。通过流式细胞术和高含量筛选定量的Annexin-V/PI测定显示，Birinapant增加了CMS 1和部分CMS 3细胞系对奥沙利铂/5-FU的反应，而CMS 2细胞未有效致敏。基于FRET的caspase-8和caspase-3激活成像在单细胞水平上验证了这些差异，在Birinapant和奥沙利铂/5-FU联合治疗期间，CMS 1细胞显示出caspase-8样活性的持续激活，最终激活了内在线粒体凋亡途径。在CMS 2细胞系中，Birinapant与TNFα联合使用时表现出协同效应，表明Birinapant可以在该亚型的炎症信号背景下恢复外源性凋亡信号。为了进一步探索这一点，我们将CMS 2和CMS 1结肠癌细胞与外周血单个核细胞共培养。在这些共培养物中，我们观察到Birinapant单次处理期间细胞死亡增加，抗TNF α中和抗体消除了这种情况。总的来说，我们的研究表明，IAP抑制是一种有前途的调节剂，奥沙利铂/5-FU的结肠直肠癌的CMS 1亚型，并可能显示前景的CMS 2亚型，这表明分子亚型可能有助于作为IAP拮抗剂在这种疾病的患者分层工具。
Colorectal cancer is a molecularly heterogeneous disease. Responses to genotoxic chemotherapy in the adjuvant or palliative setting vary greatly between patients, and colorectal cancer cells often resist chemotherapy by evading apoptosis. Antagonists of an inhibitor of apoptosis proteins (IAPs) can restore defective apoptosis signaling by degrading cIAP1 and cIAP2 proteins and by inhibition of XIAP. Due to the multiple molecular mechanisms-of-action of these targets, responses to IAP antagonist may differ between molecularly distinct colon cancer cells. In this study, responses to the IAP antagonist Birinapant and oxaliplatin/5-fluorouracil (5-FU) were investigated in 14 colon cancer cell lines, representing the consensus molecular subtypes (CMS). Treatment with Birinapant alone did not result in a substantial increase in apoptotic cells in this cell line panel. Annexin-V/PI assays quantified by flow cytometry and high-content screening showed that Birinapant increased responses of CMS1 and partially CMS3 cell lines to oxaliplatin/5-FU, whereas CMS2 cells were not effectively sensitized. FRET-based imaging of caspase-8 and -3 activation validated these differences at the single-cell level, with CMS1 cells displaying sustained activation of caspase-8-like activity during Birinapant and oxaliplatin/5-FU co-treatment, ultimately activating the intrinsic mitochondrial apoptosis pathway. In CMS2 cell lines, Birinapant exhibited synergistic effects in combination with TNFα, suggesting that Birinapant can restore extrinsic apoptosis signaling in the context of inflammatory signals in this subtype. To explore this further, we co-cultured CMS2 and CMS1 colon cancer cells with peripheral blood mononuclear cells. We observed increased cell death during Birinapant single treatment in these co-cultures, which was abrogated by anti-TNFα-neutralizing antibodies. Collectively, our study demonstrates that IAP inhibition is a promising modulator of response to oxaliplatin/5-FU in colorectal cancers of the CMS1 subtype, and may show promise as in the CMS2 subtype, suggesting that molecular subtyping may aid as a patient stratification tool for IAP antagonists in this disease.
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影响因子：
4.6
作者：
Allen WL;Dunne PD;McDade S;Scanlon E;Loughrey M;Coleman H;McCann C;McLaughlin K;Nemeth Z;Syed N;Jithesh P;Arthur K;Wilson R;Coyle V;McArt D;Murray GI;Samuel L;Nuciforo P;Jimenez J;Argiles G;Dienstmann R;Tabernero J;Messerini L;Nobili S;Mini E;Sheahan K;Ryan E;Johnston PG;Van Schaeybroeck S;Lawler M;Longley DB
通讯作者：
Longley DB
影响因子：
9.8
作者：
Albeck JG;Burke JM;Spencer SL;Lauffenburger DA;Sorger PK
通讯作者：
Sorger PK
影响因子：
16
作者：
Bertrand, Mathieu J. M.;Milutinovic, Snezana;Barker, Philip A.
通讯作者：
Barker, Philip A.
DOI：
10.1158/1078-0432.ccr-12-0605
发表时间：
2012-12-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Gavin PG;Colangelo LH;Fumagalli D;Tanaka N;Remillard MY;Yothers G;Kim C;Taniyama Y;Kim SI;Choi HJ;Blackmon NL;Lipchik C;Petrelli NJ;O'Connell MJ;Wolmark N;Paik S;Pogue-Geile KL
通讯作者：
Pogue-Geile KL
FOLFOX辅助化疗的III期结直肠癌的预后可以通过分子亚型进行预测。
影响因子：
--
作者：
Kwon Y;Park M;Jang M;Yun S;Kim WK;Kim S;Paik S;Lee HJ;Hong S;Kim TI;Min B;Kim H
通讯作者：
Kim H