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Tumor Biology

, Volume 37, Issue 6, pp 7535–7546 | Cite as

Upregulation of connexin43 contributes to PX-12-induced oxidative cell death

  • Gang Li
  • Kun Gao
  • Yuan Chi
  • Xiling Zhang
  • Takahiko Mitsui
  • Jian YaoEmail author
  • Masayuki Takeda
Original Article

Abstract

Thioredoxin (Trx) is a small redox protein that underlies aggressive tumor growth and resistance to chemotherapy. Inhibition of Trx with the chemical inhibitor PX-12 suppresses tumor growth and induces cell apoptosis. Currently, the mechanism underlying the therapeutic actions of PX-12 and the molecules influencing cell susceptibility to PX-12 are incompletely understood. Given that connexin43 (Cx43), a tumor suppressor, regulates tumor cell susceptibility to chemotherapy, we examined the possible involvement of Cx43 in PX-12-induced cell death. Exposure of cells to PX-12 led to a loss of cell viability, which was associated with the activation of oxidative sensitive c-Jun N-terminal kinase (JNK). Inhibition of JNK or supplement of cells with anti-oxidants prevented the cell-killing action of PX-12. The forced expression of Cx43 in normal and tumor cells increased cell sensitivity to PX-12-induced JNK activation and cell death. In contrast, the downregulation of Cx43 with siRNA or the suppression of gap junctions with chemical inhibitors attenuated JNK activation and enhanced cell resistance to PX-12. Further analysis revealed that PX-12 at low concentrations induced a JNK-dependent elevation in the Cx43 protein, which was also preventable by supplementing the cells with anti-oxidants. Our results thus indicate that Cx43 is a determinant in the regulation of cell susceptibility to PX-12 and that the upregulation of Cx43 may be an additional mechanism by which PX-12 exerts its anti-tumor actions.

Keywords

Cx43 PX-12 Thioredoxin JNK Oxidative stress 

Abbreviations

NAC

N-Acetyl-1-cysteine

CA

Carbenoxolone

Cx

Connexin

EGFP

Enhanced green fluorescent protein

GJ

Gap junction

GSH

Glutathione reduced ethyl ester

α-GA

α-Glycyrrhetinic acid

LDH

Lactate dehydrogenase

PI

Propidium iodide

ROS

Reactive oxygen species

Trx

Thioredoxin

WT

Wild type

Notes

Acknowledgments

This work was supported by Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology, Japan (to 26461219 to J.Y.) and by a grant from the National Natural Science Foundation of China (Grant 81302918 to K.G.).

Compliance with ethical standards

Conflicts of interest

None

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Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  • Gang Li
    • 1
    • 2
    • 3
  • Kun Gao
    • 1
  • Yuan Chi
    • 1
  • Xiling Zhang
    • 1
  • Takahiko Mitsui
    • 2
  • Jian Yao
    • 1
    Email author
  • Masayuki Takeda
    • 2
  1. 1.Department of Molecular Signaling, Interdisciplinary Graduate School of Medicine and EngineeringUniversity of YamanashiChuoJapan
  2. 2.Department of Urology, Interdisciplinary Graduate School of Medicine and EngineeringUniversity of YamanashiChuoJapan
  3. 3.Department of Urology, Liaoning Cancer Hospital and InstituteCancer Hospital of China Medical UniversityShenyangChina

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