Investigating the Impact of Mitochondrial Mutations on Chemotherapy Resistance in Cervical Cancer

Subject Areas : genetics

Ayat Mohebifar ¹ , Katayoun Mayeli ² , Saber Safinejad ³ , kyumars safinejad ⁴

1 - PhD Student, Young and Elite Researchers Club, Department of Biology, Faculty of Science, Islamic Azad University, Varamin Branch, Pishva, Tehran, Iran
2 - MS, Department of Biology, Faculty of Science, East Tehran Branch, Islamic Azad University, Tehran, Iran.
3 - Department of Basic Sciences, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran
4 - Assistant Prof ,Department of Biology, Faculty of Science, Borujerd Branch, Islamic Azad University, Borujerd, Iran.

Received: 2025-03-16 Accepted : 2025-06-01 Published : 2025-06-01

Keywords: Cervical cancer, chemotherapy resistance, mitochondrial DNA mutations,

Abstract :

Introduction: Cervical cancer is one of the most common malignancies in women, with chemotherapy serving as a primary treatment modality. However, the emergence of drug resistance in some patients reduces treatment efficacy. Studies indicate that mitochondrial DNA (mtDNA) mutations may play a role in regulating energy metabolism and cellular stress responses. This study aimed to investigate the impact of A1555G, A3243G, and A7445G mtDNA mutations on chemotherapy resistance in cervical cancer patients.

Materials and Methods: This study included 100 cervical cancer patients undergoing chemotherapy and 100 healthy controls. DNA was extracted using the phenol-chloroform method. Target mutations were analyzed via PCR-RFLP and confirmed by sequencing. The association between mutations and treatment response was evaluated using statistical tests.

Results: Results demonstrated that the A3243G mutation was significantly associated with increased chemotherapy resistance (P<0.05). In contrast, A1555G and A7445G mutations showed no significant correlation with drug resistance (P>0.05).

Conclusion: This study suggests the A3243G mutation may serve as a potential biomarker for predicting chemotherapy resistance in cervical cancer patients. A deeper understanding of the underlying mechanisms could facilitate the development of personalized treatment strategies and enhance the efficacy of anticancer therapies.

References:

1. Sung, H., Ferlay, J., Siegel, R. L., Laversanne, M., Soerjomataram, I., Jemal, A., & Bray, F.. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA: a cancer journal for clinicians, 2021; 71(3), 209–249. DOI: 10.3322/caac.21660
2. Bray, F., Ferlay, J., Soerjomataram, I., Siegel, R. L., Torre, L. A., & Jemal, A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: A Cancer Journal for Clinicians, 2018; 68(6), 394-424. DOI: 10.3322/caac.21492
3. Fadaei, R., & Alizadeh, R. Cervical cancer incidence and its risk factors in Iran: A nationwide study. Iranian Journal of Cancer Prevention, 2020; 13(2), e9559. DOI: 10.17795/ijcp-9559
4. Sharma, S., & Rao, A. Cisplatin and paclitaxel as treatment strategies in cervical cancer: A review. Journal of Cancer Research & Clinical Oncology, 2019; 145(3(, 567-576. DOI: 10.1007/s00432-019-02814-5
5. Holohan, C., van Schaeybroeck, S., Longley, D. B., & Johnston, P. G. Cancer drug resistance: An evolving paradigm. Nature Reviews Cancer, 2013; 13(10(, 714-726. DOI: 10.1038/nrc3599
6. Chao, S. P., & Chen, C. Y. Molecular mechanisms of drug resistance in cervical cancer: Advances and future perspectives. Oncology Letters, 2021; 22(2), 1-9. DOI: 10.3892/ol.2021.12837
7. Chandra, S., & Lee, A. Mitochondrial mutations and their role in cancer development and therapy resistance. Journal of Mitochondrial Medicine, 2020; 12(2), 67-78. DOI: 10.1007/s12272-020-01271-4
8. Wu, Y., & Liang, X. Mitochondrial DNA mutations in cancer: Potential as biomarkers for therapy resistance. Molecular Cancer Research, 2018; 16(3), 508-520. DOI: 10.1158/1541-7786.MCR-17-0544
9. Dhingra, S., & Zareen, N. Mitochondrial mutations and their roles in cancer metastasis. Cellular and Molecular Life Sciences, 2019; 76(8), 1691-1702. DOI: 10.1007/s00018-018-2905-2
10. Lee, D. H., & Park, T. K. Bioinformatics approaches in understanding drug resistance in cancer: Recent advances. Bioinformatics, 2020; 36(8), 2561-2570. DOI: 10.1093/bioinformatics/btz976
11. Xu, W., Liu, K., Li, Y., & Zhao, P. Mechanisms of apoptosis induced by natural plant compounds in cancer therapy. Molecular Cancer, 2025; 21(1), 30-44. DOI: 10.1186/s12885-020-01569-2
12. Sharma, V., Anderson, D., & Dhawan, A. Zinc oxide nanoparticles induce oxidative DNA damage and ROS-triggered mitochondria-mediated apoptosis in human liver cells (HepG2). Apoptosis, 2023; 25(1-2), 54-68. DOI: 10.1007/s10495-019-01541-9
13. Chou, C. H., Lin, C. H., & Chiu, Y. C. The role of oxidative stress in regulating the apoptosis pathway in breast cancer cell lines. Free Radical Biology and Medicine, 2024; 180, 215-234. DOI: 10.1016/j.freeradbiomed.2022.05.006
14. Shu, H.Y., H.C. Li, W.Q. Xie, B. Ni and H.Y.Z. Zhou . Mitochondrial DNA variations in tongue squamous cell carcinoma. Bimed Rep. 2019; 10(1): 23-28. DOI:10.3892/br.2018.1167
15. Vyas, S., E. Zaganjor and M.C. Haigis. Mitochondria and Cancer. 2016; Cell, 166: 555-566. DOI:10.1016/j.cell.2016.07.002.
16. Maa, Y., F. Fang and Y. Yang . The study of mitochondrial A3243G mutation in different samples Mitochondrion, 2009; 9: 139-43. DOI: 10.1016/j.mito.2009.01.004
17. Bonora, M., Morganti, C., Morciano, G., Giorgi, C., Wieckowski, M. R., & Pinton, P. (2016). Comprehensive analysis of mitochondrial permeability transition pore activity in living cells using fluorescence-imaging-based techniques. Nature protocols, 11(6), 1067–1080. DOI:10.1038/nprot.2016.064

18. Porporato, P.E., N. Filigheddu, J.M. Bravo-San Pedro and G. Kroemer. Mitochondrial metabolism and cancer. Cell Research, 2018; 28: 265-280. DOI:10.1038/cr.2017.155
19. Prezant, T.R., J.V. Agapian, M.C. Bohlman, X. Bu, S. Oztas and W.Q. Qiu . Mitochondrial ribosomal RNA mutation associated with both antibiotic-induced and non-syndromic deafness. Nat Genet., 1993; 4(3): 289-94 DOI:10.1038/ng0793-289.
20. Schapira A. H. Mitochondrial diseases. Lancet (London, England), 2012; 379(9828), 1825–1834. DOI:10.1016/S0140-6736(11)61305-6