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Mitochondrial DNA mutations are involved in the acquisition of cisplatin resistance in human lung cancer A549 cells

  • Authors:
    • Sayo Horibe
    • Kaori Ishikawa
    • Kazuto Nakada
    • Masaki Wake
    • Norihiko Takeda
    • Toru Tanaka
    • Shoji Kawauchi
    • Naoto Sasaki
    • Yoshiyuki Rikitake
  • View Affiliations / Copyright

    Affiliations: Laboratory of Medical Pharmaceutics, Kobe Pharmaceutical University, Higashinada‑ku, Kobe, Hyogo 658‑8558, Japan, Faculty of Life and Environmental Sciences, University of Tsukuba, Tennodai, Tsukuba, Ibaraki 305‑8572, Japan, Division of Cardiology and Metabolism, Center for Molecular Medicine, Jichi Medical University, Yakushiji, Shimotsuke‑shi, Tochigi 329‑0498, Japan, Comprehensive Education and Research Center, Kobe Pharmaceutical University, Higashinada‑ku, Kobe, Hyogo 658‑8558, Japan
    Copyright: © Horibe et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 32
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    Published online on: December 20, 2021
       https://doi.org/10.3892/or.2021.8243
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Abstract

The efficacy of cisplatin (CDDP) has been demonstrated in the treatment of various cancers as monotherapy and combination therapy with immunotherapy. However, acquired CDDP resistance is a major obstacle to successful treatment. In the present study, the mechanisms underlying acquired CDDP resistance were examined using ACR20 cells, which are CDDP‑resistant cells derived from A549 lung cancer cells. CDDP induces cytotoxicity by binding nuclear DNA and generating reactive oxygen species (ROS). Contrary to our expectation, ROS levels were elevated in ACR20 cells not treated with CDDP. Pretreatment with an ROS inhibitor enhanced the sensitivity of ACR20 cells to CDDP and prevented the activation of nuclear factor (NF)‑кB signaling and upregulation of inhibitor of apoptosis proteins (IAPs). Notably, evaluation of the mitochondrial oxygen consumption rate and mitochondrial superoxide levels revealed a deterioration of mitochondrial function in ACR20 cells. Mitochondrial DNA PCR‑RFLP analysis revealed four mutations with varying percentage levels in ACR20 cells. In addition, in cytoplasmic hybrids with mitochondria from ACR20 cells, intrinsic ROS levels were elevated, expression of IAPs was increased, and complex I activity and sensitivity to CDDP were decreased. Analysis of three‑dimensional structure data indicated that a mutation (ND2 F40L) may impact the proton translocation pathway, thereby affecting mitochondrial complex I activity. Together, these findings suggest that intrinsic ROS levels were elevated by mitochondrial DNA mutations, which decreased the sensitivity to CDDP via activation of NF‑κB signaling and induction of IAP expression in ACR20 cells. These findings indicate that newly identified mutations in mitochondrial DNA may lead to acquired cisplatin resistance in cancer.
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Copy and paste a formatted citation
Spandidos Publications style
Horibe S, Ishikawa K, Nakada K, Wake M, Takeda N, Tanaka T, Kawauchi S, Sasaki N and Rikitake Y: Mitochondrial DNA mutations are involved in the acquisition of cisplatin resistance in human lung cancer A549 cells. Oncol Rep 47: 32, 2022.
APA
Horibe, S., Ishikawa, K., Nakada, K., Wake, M., Takeda, N., Tanaka, T. ... Rikitake, Y. (2022). Mitochondrial DNA mutations are involved in the acquisition of cisplatin resistance in human lung cancer A549 cells. Oncology Reports, 47, 32. https://doi.org/10.3892/or.2021.8243
MLA
Horibe, S., Ishikawa, K., Nakada, K., Wake, M., Takeda, N., Tanaka, T., Kawauchi, S., Sasaki, N., Rikitake, Y."Mitochondrial DNA mutations are involved in the acquisition of cisplatin resistance in human lung cancer A549 cells". Oncology Reports 47.2 (2022): 32.
Chicago
Horibe, S., Ishikawa, K., Nakada, K., Wake, M., Takeda, N., Tanaka, T., Kawauchi, S., Sasaki, N., Rikitake, Y."Mitochondrial DNA mutations are involved in the acquisition of cisplatin resistance in human lung cancer A549 cells". Oncology Reports 47, no. 2 (2022): 32. https://doi.org/10.3892/or.2021.8243
Copy and paste a formatted citation
x
Spandidos Publications style
Horibe S, Ishikawa K, Nakada K, Wake M, Takeda N, Tanaka T, Kawauchi S, Sasaki N and Rikitake Y: Mitochondrial DNA mutations are involved in the acquisition of cisplatin resistance in human lung cancer A549 cells. Oncol Rep 47: 32, 2022.
APA
Horibe, S., Ishikawa, K., Nakada, K., Wake, M., Takeda, N., Tanaka, T. ... Rikitake, Y. (2022). Mitochondrial DNA mutations are involved in the acquisition of cisplatin resistance in human lung cancer A549 cells. Oncology Reports, 47, 32. https://doi.org/10.3892/or.2021.8243
MLA
Horibe, S., Ishikawa, K., Nakada, K., Wake, M., Takeda, N., Tanaka, T., Kawauchi, S., Sasaki, N., Rikitake, Y."Mitochondrial DNA mutations are involved in the acquisition of cisplatin resistance in human lung cancer A549 cells". Oncology Reports 47.2 (2022): 32.
Chicago
Horibe, S., Ishikawa, K., Nakada, K., Wake, M., Takeda, N., Tanaka, T., Kawauchi, S., Sasaki, N., Rikitake, Y."Mitochondrial DNA mutations are involved in the acquisition of cisplatin resistance in human lung cancer A549 cells". Oncology Reports 47, no. 2 (2022): 32. https://doi.org/10.3892/or.2021.8243
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