Human Cell

, Volume 32, Issue 1, pp 41–50 | Cite as

LRRC8A potentiates temozolomide sensitivity in glioma cells via activating mitochondria-dependent apoptotic pathway

  • Chao Yang
  • Longshuang He
  • Gaofei Chen
  • Zeqian Ning
  • Zhibai XiaEmail author
Research Article


Chloride (Cl), a primary anion in the extracellular fluid, plays an important role in a variety of physiological and pathological processes, such as cell apoptosis and proliferation. However, the information about Cl in cancer cell apoptosis and chemoresistance is poorly understood. In the present study, we found that temozolomide (TMZ) treatment led to a decrease in intracellular concentration of Cl ([Cl]i) in both U87 and TMZ-resistant U87/R glioma cells. The decrease in [Cl]i was more noticeable in U87 cells than in U87/R cells. Moreover, the expression of LRRC8A was reduced in U87/R cells compared with U87 cells. LRRC8A downregulation inhibited TMZ, induced the decrease in [Cl]i and abolished the difference of [Cl]i between U87 cells and U87/R cells. Knockdown of LRRC8A using small interfering RNA attenuated TMZ-induced U87 cell growth inhibition and apoptosis, while overexpression of LRRC8A by adenoviral infection enhanced the effect of TMZ on U87 and U87/R cell viability and apoptosis. Furthermore, LRRC8A downregulation inhibited TMZ-induced mitochondria-dependent apoptosis, including elevated Bcl-2 expression, reduced Bax expression, cytochrome c release, and caspase nine and caspase three activation. On the contrary, upregulation of LRRC8A augmented the activation of mitochondria-dependent apoptotic pathway in U87 and U87/R cells. In conclusion, this study demonstrates that LRRC8A potentiates TMZ-induced glioma cell apoptosis via promoting mitochondria-dependent apoptosis, suggesting that LRRC8A can be represented as a novel target for drug resistance treatment in glioma cells.


Drug resistance Glioma Chloride LRRC8A Mitochondrial apoptosis Temozolomide 


Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

13577_2018_221_MOESM1_ESM.docx (348 kb)
Supplementary material 1 (DOCX 347 KB)


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Copyright information

© Japan Human Cell Society and Springer Japan KK, part of Springer Nature 2018

Authors and Affiliations

  • Chao Yang
    • 1
  • Longshuang He
    • 2
  • Gaofei Chen
    • 3
  • Zeqian Ning
    • 2
  • Zhibai Xia
    • 1
    Email author
  1. 1.Department of NeurosurgeryThe First Affiliated Hospital of Sun Yat-Sen UniversityGuangzhouChina
  2. 2.Department of NeurosurgeryThe First Affiliated Hospital of Guangdong Pharmaceutical UniversityGuangzhouChina
  3. 3.School of NursingGuangdong Pharmaceutical UniversityGuangzhouChina

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