Role and mechanism of hexokinase 2 in erlotinib resistance in non-small cell lung cancer

Qi YOU; Wenlei ZHUO; Zhengtang CHEN

doi:10.16016/j.1000-5404.201912141

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Role and mechanism of hexokinase 2 in erlotinib resistance in non-small cell lung cancer

Basic Medicine | 更新时间：2026-01-09

- Role and mechanism of hexokinase 2 in erlotinib resistance in non-small cell lung cancer
- Journal of Third Military Medical University Vol. 42, Issue 5, Pages: 453-459(2020)
- 作者机构：
  
  400037 重庆，陆军军医大学(第三军医大学)第二附属医院全军肿瘤研究所
- 作者简介：
- 基金信息：
  
  Supported by the General Program of National Natural Science Foundation of China(81672290);the Key Supporting Project of Talent Bank Funded by Army Medical University(2019)
- DOI：10.16016/j.1000-5404.201912141
  CLC： R345;R730.23;R737.9
- Received：16 December 2019，
  
  Revised：2020-01-25，
  
  Published：15 March 2020
- 稿件说明：
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Qi YOU, Wenlei ZHUO, Zhengtang CHEN. Role and mechanism of hexokinase 2 in erlotinib resistance in non-small cell lung cancer[J]. Journal of Third Military Medical University, 2020, 42(5): 453-459.
DOI：

Qi YOU, Wenlei ZHUO, Zhengtang CHEN. Role and mechanism of hexokinase 2 in erlotinib resistance in non-small cell lung cancer[J]. Journal of Third Military Medical University, 2020, 42(5): 453-459. DOI： 10.16016/j.1000-5404.201912141.

摘要

目的

观察糖酵解关键酶己糖激酶2(hexokinase 2，HK2)在人非小细胞肺癌(non-small cell lung cancer

NSCLC)组织中的表达，探讨HK2在NSCLC厄洛替尼耐药中的作用及机制。

方法

在线数据库分析肺癌组织中HK2的表达与预后的关系以及厄洛替尼对NSCLC HK2基因表达的影响；q-PCR体外验证HK2在正常肺上皮细胞、肺癌细胞中的表达差异；q-PCR、Western blot检测厄洛替尼敏感细胞(PC9)、耐药细胞(PC9/ER)中HK2的基础表达以及厄洛替尼干预后HK2的表达情况；进而使用HK2抑制剂3-溴丙酮酸处理PC9/ER，采用CCK-8法检测PC9/ER耐药性、流式细胞术分析PC9/ER的增殖能力。

结果

HK2与肺癌患者预后不良相关，HK2高表达组患者的总体生存期(overall survival

OS)较低表达组明显缩短(

0.05)；细胞实验证实HK2在PC9/ER中相对高表达，且厄洛替尼可降低PC9细胞中HK2的表达，而对PC9/ER细胞HK2的表达无显著影响；3-溴丙酮酸可有效抑制PC9/ER中HK2的表达，CCK-8法结果表明，PC9/ER 3-溴丙酮酸处理组厄洛替尼IC

值较PC9/ER对照组显著降低，提示3-溴丙酮酸处理后能让耐药的PC9/ER细胞恢复对厄洛替尼的敏感性；3-溴丙酮酸处理组增殖指数为(14.1±0.8)%，较对照组(30.4±2.3)%显著减少(

=0.008)，提示3-溴丙酮酸能明显抑制耐药细胞增殖。

结论

HK2是NSCLC患者的不良预后指标，可诱导NSCLC厄洛替尼耐药。可能和其促进糖酵解的机制有关，抑制其表达有望成为逆转NSCLC厄洛替尼耐药的有效策略。

Abstract

Objective

To observe the expression of hexokinase 2 (HK2)

a key enzyme of glycolysis

in human non-small cell lung cancer (NSCLC) tissues

and to investigate the role and mechanism of HK2 in the resistance of NSCLC to erlotinib.

Methods

The relationship between the expression of HK2 and prognosis in lung cancer and the effect of erlotinib on NSCLC HK2 gene exlpression were analyzed through online databases (Kaplan-Meier Plotter

GEPIA and GEO DataSets). q-PCR was used to verify the expression differences of HK2 in normal lung epithelial cells and lung cancer cells

in vitro

. The basic expression of HK2 in erlotinib-sensitive cells (PC9) and erlotinib-resistant cells (PC9/ER) and the expression of HK2 after erlotinib intervention were detected by q-PCR and Western blotting. After 3-bromopyruvate

a HK2 inhibitor

was used to treat PC9/

ER cells

the erlotinib resistance and cell proliferation in PC9/ER cells were detected by CCK-8 assay and flow cytometry.

Results

HK2 was associated with poor prognosis in NSCLC patients

and overall survival (OS) in the group with high expression of HK2 was significantly shortened when compared with the group with low expression (

0.05). Cell experiments confirmed that HK2 was relatively highly expressed in PC9/ER cells

and erlotinib treatment could reduce HK2 expression in PC9 cells

but had no significant effect on PC9/ER cells. 3-bromopyruvate successfully inhibited the expression of HK2 in PC9/ER cells. CCK-8 assay showed that IC

value of erlotinib was significantly lower in the PC9/ER 3-bromopyruvate treated group than the PC9/ER control group (0.005±0.001

1.967±0.436 μmol/L

=0.016)

suggesting that the inhibitor treatment can restore the sensitivity of PC9/ER cells to erlotinib. In addition

the treatment also resulted in significantly decreased proliferation index in the 3-bromopyruvate treatment group than the control group [(14.1±0.8)%

(30.4±2.3)%

=0.008)

indicating that the inhibitor could significantly inhibit the proliferation of drug-resistant cells.

Conclusion

HK2 is an indicator for poor prognosis in NSCLC patients. It can induce erlotinib resistance to NSCLC

which may be associated with its promotion in glycolysis

and inhibiting its expression may be an effective strategy to reverse erlotinib resistance in NSCLC.

关键词

Keywords

references

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