Aspirin reprogrammes colorectal cancer cell metabolism and sensitises to glutaminase inhibition.
Aspirin reprogrammes colorectal cancer cell metabolism and sensitises to glutaminase inhibition.
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DOI：
10.1186/s40170-023-00318-y
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发表时间：
2023-10-19
影响因子：
5.9
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中科院分区：
文献类型：
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为了在具有挑战性的微环境中支持增殖和存活，癌细胞必须重新编程其代谢。因此，靶向癌细胞代谢是一种有前途的治疗途径。然而，由于癌细胞的代谢可塑性，识别癌细胞中代谢脆弱性的易处理节点具有挑战性。确定有效的治疗组合，以应对这是一个活跃的研究领域。阿司匹林在癌症预防中具有公认的作用，特别是在结直肠癌（CRC）中，尽管其机制尚未完全清楚。我们生成了一个模型来研究长期（52周）阿司匹林暴露对CRC细胞的影响，这使得我们能够使用蛋白质组学，海马细胞外通量分析和稳定同位素标记（SIL）全面验证长期阿司匹林暴露（2- 4 mM，持续52周）的代谢影响。利用这些信息，我们能够确定代谢脆弱性的节点，以进一步靶向，研究阿司匹林与代谢抑制剂在体外和体内联合使用的影响。我们表明，阿司匹林调节几种酶和转运中心碳代谢，并导致减少在reacaminolysis和葡萄糖代谢的伴随增加，表明重新编程的营养利用。我们发现阿司匹林可能引起代偿性变化，使细胞对谷胱甘肽转移酶1（GLS 1）转运蛋白CB-839敏感。值得注意的是，考虑到临床意义，单独用CB-839治疗对CRC细胞生长或存活几乎没有影响。然而，与阿司匹林组合，CB-839在体外抑制CRC细胞增殖并诱导细胞凋亡，重要的是，在体内减少Apcfl/fl小鼠中的隐窝增殖。总之，这些结果表明，阿司匹林导致结直肠癌细胞中显著的代谢重编程，并提高了阿司匹林可以显着提高CRC代谢癌症治疗疗效的可能性。在线版本包含补充材料，可通过10.1186/s40170-023-00318-y获得。
To support proliferation and survival within a challenging microenvironment, cancer cells must reprogramme their metabolism. As such, targeting cancer cell metabolism is a promising therapeutic avenue. However, identifying tractable nodes of metabolic vulnerability in cancer cells is challenging due to their metabolic plasticity. Identification of effective treatment combinations to counter this is an active area of research. Aspirin has a well-established role in cancer prevention, particularly in colorectal cancer (CRC), although the mechanisms are not fully understood. We generated a model to investigate the impact of long-term (52 weeks) aspirin exposure on CRC cells, which has allowed us comprehensively characterise the metabolic impact of long-term aspirin exposure (2–4mM for 52 weeks) using proteomics, Seahorse Extracellular Flux Analysis and Stable Isotope Labelling (SIL). Using this information, we were able to identify nodes of metabolic vulnerability for further targeting, investigating the impact of combining aspirin with metabolic inhibitors in vitro and in vivo. We show that aspirin regulates several enzymes and transporters of central carbon metabolism and results in a reduction in glutaminolysis and a concomitant increase in glucose metabolism, demonstrating reprogramming of nutrient utilisation. We show that aspirin causes likely compensatory changes that render the cells sensitive to the glutaminase 1 (GLS1) inhibitor—CB-839. Of note given the clinical interest, treatment with CB-839 alone had little effect on CRC cell growth or survival. However, in combination with aspirin, CB-839 inhibited CRC cell proliferation and induced apoptosis in vitro and, importantly, reduced crypt proliferation in Apcfl/fl mice in vivo. Together, these results show that aspirin leads to significant metabolic reprogramming in colorectal cancer cells and raises the possibility that aspirin could significantly increase the efficacy of metabolic cancer therapies in CRC. The online version contains supplementary material available at 10.1186/s40170-023-00318-y.
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影响因子：
168.9
作者：
Burn, John;Gerdes, Anne-Marie;Macrae, Finlay;Mecklin, Jukka-Pekka;Moeslein, Gabriela;Olschwang, Sylviane;Eccles, Diane;Evans, D. Gareth;Maher, Eamonn R.;Bertario, Lucio;Bisgaard, Marie-Luise;Dunlop, Malcolm G.;Ho, Judy W. C.;Hodgson, Shirley V.;Lindblom, Annika;Lubinski, Jan;Morrison, Patrick J.;Murday, Victoria;Ramesar, Raj;Side, Lucy;Scott, Rodney J.;Thomas, Huw J. W.;Vasen, Hans F.;Barker, Gail;Crawford, Gillian;Elliott, Faye;Movahedi, Mohammad;Pylvanainen, Kirsi;Wijnen, Juul T.;Fodde, Riccardo;Lynch, Henry T.;Mathers, John C.;Bishop, D. Timothy
通讯作者：
Bishop, D. Timothy
影响因子：
11.2
作者：
Henry WS;Laszewski T;Tsang T;Beca F;Beck AH;McAllister SS;Toker A
通讯作者：
Toker A
影响因子：
5.9
作者：
Dupuy F;Griss T;Blagih J;Bridon G;Avizonis D;Ling C;Dong Z;Siwak DR;Annis MG;Mills GB;Muller WJ;Siegel PM;Jones RG
通讯作者：
Jones RG
DOI：
10.1073/pnas.1312570111
发表时间：
2014-02-18
影响因子：
11.1
作者：
Faubert, Brandon;Vincent, Emma E.;Jones, Russell G.
通讯作者：
Jones, Russell G.
影响因子：
3
作者：
Cao, Yong;Lin, Yan;Zheng, Changqing
通讯作者：
Zheng, Changqing