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

Ma,Lijie; Wang,Ruixuan; Duan,Hongtao; Nan,Yandong; Wang,Qingwei; Jin,Faguang

doi:10.3892/or.2015.4315

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

Authors:
- Lijie Ma
- Ruixuan Wang
- Hongtao Duan
- Yandong Nan
- Qingwei Wang
- Faguang Jin
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Affiliations: Department of Respiration, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710038, P.R. China, Department of Thoracic Surgery, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710038, P.R. China, Department of Pharmacy, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710038, P.R. China
Published online on: September 30, 2015 https://doi.org/10.3892/or.2015.4315
Pages: 3238-3246

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Abstract

Small cell lung cancer (SCLC) accounts for ~15% of all lung cancer cases, and chemotherapy has dramatically improved the survival rate of SCLC patients. Yet, the long-term survival rate of this cancer has not improved since multi-drug resistance (MDR) may emerge after chemotherapy. Mitochondrial DNA (mtDNA) mutation-related biological processes, such as energy metabolism and reactive oxygen species (ROS) production, have been considered to be associated with tumorigenesis and drug resistance. It was hypothesized and demonstrated, in the present study, that mitochondrial dysfunction is the reason for the occurrence and progression of SCLC. mtDNA from drug sensitive and drug insensitive cell lines (H446 and H446/CDDP) was sequenced and compared with the revised Cambridge reference sequence (rCRS). The results revealed that there was no difference in the mtDNA sequence from H446 and H446/CDDP cells, but several spot mutations were observed according to that of rCRs. Further evaluation on mitochondrial function revealed that H446 cells synthesized and secreted more lactic acid and ROS compared with that of H446/CDDP cells when challenged by the same dose of cisplatin (P>0.05). In addition, examination of the mitochondrial apoptotic pathway indicated that more Bax, cleaved caspase-3 and cleaved caspase-9 were expressed in H446 cells compared with that of H446/CDDP cells when stimulated by the same dose of cisplatin (P>0.05). In conclusion, the results of the present study revealed that mtDNA mutations were responsible for the tumorigenesis of SLCL, but not associated with the drug sensitivity of SCLC cell lines. On the other hand, varied mitochondrium content‑related mitochondrial dysfunction participated in the MDR of SCLC possibly by affecting the ROS-mediated mitochondrial apoptotic pathway.

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