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Lactate dehydrogenase inhibition affects homologous recombination repair independently of cell metabolic asset; implications for anticancer treatment
Biochimica et Biophysica Acta (BBA) - General Subjects ( IF 3 ) Pub Date : 2020-10-07 , DOI: 10.1016/j.bbagen.2020.129760
Andrea Balboni , Marzia Govoni , Valentina Rossi , Marinella Roberti , Andrea Cavalli , Giuseppina Di Stefano , Marcella Manerba

Background

Cancer cells show highly increased glucose utilization which, among other cancer-essential functions, was found to facilitate DNA repair. Lactate dehydrogenase (LDH) activity is pivotal for supporting the high glycolytic flux of cancer cells; to our knowledge, a direct contribution of this enzyme in the control of DNA integrity was never investigated. In this paper, we looked into a possible LDH-mediated regulation of homologous recombination (HR) repair.

Methods

We identified two cancer cell lines with different assets in energy metabolism: either based on glycolytic ATP or on oxidative reactions. In cells with inhibited LDH, we assessed HR function by applying four different procedures.

Results

Our findings revealed an LDH-mediated control of HR, which was observed independently of cell metabolic asset. Since HR inhibition is known to make cancer cells responsive to PARP inhibitors, in both the cellular models we finally explored the effects of a combined inhibition of LDH and PARP.

Conclusions

The obtained results suggest for LDH a central role in cancer cell biology, not merely linked to the control of energy metabolism. The involvement of LDH in the DNA damage response could suggest new drug combinations to obtain improved antineoplastic effects.

General significance

Several evidences have correlated the metabolic features of cancer cells with drug resistance and LDH inhibition has been repeatedly shown to increase the antineoplastic power of chemotherapeutics. By shedding light on the processes linking cell metabolism to the control of DNA integrity, our findings also give a mechanistic explanation to these data.



中文翻译:

乳酸脱氢酶抑制作用独立于细胞代谢资产而影响同源重组修复;对抗癌治疗的意义

背景

癌细胞显示出葡萄糖利用的高度增加,其中葡萄糖具有其他重要的癌症功能,可促进DNA修复。乳酸脱氢酶(LDH)活性对于支持癌细胞的高糖酵解通量至关重要。据我们所知,从未研究过这种酶在控制DNA完整性方面的直接作用。在本文中,我们研究了可能的LDH介导的同源重组(HR)修复调控。

方法

我们确定了两种在能量代谢中具有不同资产的癌细胞系:基于糖酵解ATP或基于氧化反应。在具有抑制的LDH的细胞中,我们通过应用四种不同的方法评估了HR功能。

结果

我们的发现揭示了LDH介导的HR控制,独立于细胞代谢资产而观察到。由于已知HR抑制作用会使癌细胞对PARP抑制剂起反应,因此在这两种细胞模型中,我们最终都探索了LDH和PARP联合抑制作用。

结论

获得的结果表明,LDH在癌细胞生物学中起着中心作用,而不仅仅是与能量代谢的控制有关。LDH参与DNA损伤反应可能表明新药组合可获得改善的抗肿瘤作用。

一般意义

一些证据已将癌细胞的代谢特征与耐药性相关联,并且反复显示出对LDH的抑制会增加化学疗法的抗肿瘤能力。通过阐明将细胞代谢与DNA完整性控制联系起来的过程,我们的发现也为这些数据提供了机械解释。

更新日期:2020-10-13
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