Effect of Metabolic Reprogramming on Toxin Eliminating Therapeutics in Targeting Lung Cancer Stem Cells

Hui-jie LI; Xi-wen HU; Yuan-fu QI; Xiu-rong LI; Zhai-dong LIU

doi:10.13422/j.cnki.syfjx.20200423

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Effect of Metabolic Reprogramming on Toxin Eliminating Therapeutics in Targeting Lung Cancer Stem Cells

Pharmacology | 更新时间：2021-02-09

- Effect of Metabolic Reprogramming on Toxin Eliminating Therapeutics in Targeting Lung Cancer Stem Cells
- Chinese Journal of Experimental Traditional Medical Formulae Vol. 26, Issue 8, Pages: 75-80(2020)
- 作者机构：
  
  山东中医药大学　附属医院，济南　 250014
- 作者简介：
- 基金信息：
- DOI：10.13422/j.cnki.syfjx.20200423
  CLC： R22; R242; R2-031;R285.5
- Received：30 June 2019，
  
  Published Online：04 November 2019，
  
  Published：20 April 2020
- 稿件说明：
移动端阅览
Hui-jie LI, Xi-wen HU, Yuan-fu QI, et al. Effect of Metabolic Reprogramming on Toxin Eliminating Therapeutics in Targeting Lung Cancer Stem Cells[J]. Chinese journal of experimental traditional medical formulae, 2020, 26(8): 75-80.
DOI：

Hui-jie LI, Xi-wen HU, Yuan-fu QI, et al. Effect of Metabolic Reprogramming on Toxin Eliminating Therapeutics in Targeting Lung Cancer Stem Cells[J]. Chinese journal of experimental traditional medical formulae, 2020, 26(8): 75-80. DOI： 10.13422/j.cnki.syfjx.20200423.

摘要

目的：

观察攻毒治法代表药物纳米雄黄靶向肺癌干细胞缺氧诱导因子(hypoxia-inducible factors

HIF)效应分子驱动代谢重编程的作用，探究肺癌干细胞、代谢重编程在肺癌转移过程中的效应机制，验证攻毒治法防治肺癌转移的有效性。

方法：

体外培养肺癌A549细胞，分选肺癌干细胞并鉴定。按空白组，顺铂(5 mg·L

-1

)组，纳米雄黄低、中、高剂量(100，200，400 mg·L

-1

)组分别干预，采用葡萄糖氧化酶法检测纳米雄黄对肺癌干细胞糖代谢的影响，实时荧光定量聚合酶链式反应(Real-time PCR)，蛋白免疫印迹法(Western blot)，酶联免疫吸附测定(ELISA)分别检测纳米雄黄对肺癌干细胞代谢重编程相关基因缺氧诱导因子-1

(HIF-1

)，C-myc，p53表达的影响，对相关蛋白HIF-1

，磷脂酰肌醇3-激酶(PI3K)，蛋白激酶B(Akt)，雷帕霉素靶蛋白(mTOR)表达的影响，对相关酶葡萄糖转运蛋白1(GLUT1)，丙酮酸脱氢酶激酶1(PDK1)，M型丙酮酸激酶(PKM)，磷酸果糖激酶(PFK)，丙酮酸脱氢酶(PDH)，乳酸脱氢酶(LDH)表达的影响。

结果：

与空白组比较，纳米雄黄可降低肺癌干细胞葡萄糖消耗，随剂量增加葡萄糖消耗不断降低，呈时间剂量依懒性(

0.01)；纳米雄黄可抑制肺癌干细胞代谢重编程关键因子HIF-1

mRNA表达(

0.05，

0.01)，并可下调C-myc mRNA，上调p53 mRNA表达(

0.05，

0.01)，抑制相关蛋白PI3K，Akt，mTOR的表达(

0.05，

0.01)，抑制相关酶GLUT1，PDK1，PFK，PKM，PDH，LDH的表达(

0.05，

0.01)，且纳米雄黄随剂量增加调控能力不断增强。

结论：

攻毒治法可通过靶向HIF效应分子驱动肺癌干细胞代谢重编程，进而抑制肺癌侵袭转移。

Abstract

Objective:

To observe the effect of realgar nanoparticles (a representative drug in toxin eliminating therapeutics) targeting hypoxia-inducible factors (HIF)

which act as effector molecules on metabolic reprogramming of lung cancer stem cells

and to explore the effect mechanism of lung cancer stem cells and metabolic reprogramming in the process of lung cancer metastasis

so as to verify the effectiveness of toxin eliminating therapeutics in the prevention and treatment of lung cancer metastasis.

Method:

Lung cancer A549 cells were cultured

in vitro

and lung cancer stem cells were then identified and selected. The stem cells were divided into blank control group

cisplatin group (5 mg·L

-1

)

realgar nanoparticles low

medium and high dose groups (100

200

400 mg·L

-1

). After intervention

glucose oxidase method was used to detect the effect of realgar nanoparticles on the glucose metabolism of lung cancer stem cells

real-time polymerase chain reaction (Real-time PCR) was used to detect the mRNA expression levels of hypoxia-inducible factors-1

(HIF-1

)

C-myc and p53

while Western blot was used to detect the expression of related proteins HIF-1

phosphatidylinositol 3-kinase (PI3K)

protein kinase B (Akt) and mammalian target of rapamycin (mTOR)

and enzyme linked immunosorbent assay (ELISA) was used to detect the glucose transporter 1 (GLUT1)

pyruvate dehydrogenase kinase 1 (PDK1)

pyruvate kinase M (PKM)

phosphofructokinase(PFK)

pyruvate dehydrogenase (PDH) and lactic dehydrogenase (LDH) expression.

Result:

As compared with the blank control group

realgar nanoparticles can reduce the glucose consumption of lung cancer stem cells

and the glucose consumption was reduced with the increase of dose in a time-and dose-dependent manner (

0.01). Realgar nanoparticles can inhibit the mRNA expression of HIF-1

a key factor in metabolic reprogramming of lung cancer stem cells (

0.05

0.01)

down-regulated C-myc mRNA and up-regulated the p53 mRNA expression (

0.05

0.01)

down-regulated protein expressions of PI3K

Akt

mTOR(

0.05

0.01)

and inhibited the expression of related enzymes GLUT1

PDK1

PFK

PKM

PDH

and LDH levels (

0.05

0.01). With the increase of dose

the regulation and control ability of realgar nanoparticles gradually increased.

Conclusion:

Toxin eliminating therapeutics can drive the metabolic reprogramming of lung cancer stem cells by targeting HIF effector molecule

and then inhibit the invasion and metastasis of lung cancer.

关键词

Keywords

references

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