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Mitochondrial dysfunction rather than mtDNA sequence mutation is responsible for the multi-drug resistance of small

Lijie Ma, Ruixuan Wang, Hongtao Duan

    Oncology Reports
    |October 28, 2015
    PubMed

    Insights

    Mitochondrial DNA mutations drive small cell lung cancer (SCLC) development. However, mitochondrial dysfunction, not mtDNA mutations, contributes to chemotherapy drug resistance in SCLC by impacting the reactive oxygen species-mediated apoptotic pathway.

    Area of Science:

    • Oncology
    • Mitochondrial Biology
    • Genetics

    Background:

    • Small cell lung cancer (SCLC) survival is limited by chemotherapy resistance.
    • Mitochondrial DNA (mtDNA) mutations are implicated in tumorigenesis and drug resistance.
    • Mitochondrial dysfunction is hypothesized to drive SCLC occurrence and progression.

    Purpose of the Study:

    • To investigate the role of mtDNA mutations in SCLC tumorigenesis.
    • To determine the association between mtDNA and SCLC drug sensitivity.
    • To explore the contribution of mitochondrial dysfunction to multidrug resistance (MDR) in SCLC.

    Main Methods:

    • Sequencing of mtDNA from drug-sensitive (H446) and drug-insensitive (H446/CDDP) SCLC cell lines.
    • Comparison of mtDNA sequences with the revised Cambridge reference sequence (rCRS).
    • Assessment of mitochondrial function, including lactic acid and reactive oxygen species (ROS) production, and analysis of the mitochondrial apoptotic pathway.

    Main Results:

    • No significant differences in mtDNA sequences were found between H446 and H446/CDDP cells, though spot mutations were observed relative to rCRS.
    • H446 cells exhibited higher lactic acid and ROS synthesis than H446/CDDP cells upon cisplatin challenge.
    • Increased expression of Bax, cleaved caspase-3, and cleaved caspase-9 was noted in H446 cells compared to H446/CDDP cells post-cisplatin stimulation.

    Conclusions:

    • mtDNA mutations are linked to SCLC tumorigenesis but not directly to drug sensitivity.
    • Mitochondrial dysfunction, potentially due to varied mitochondrium content, contributes to SCLC multidrug resistance.
    • The ROS-mediated mitochondrial apoptotic pathway is a key factor in SCLC drug resistance.

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