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Role of NRF2 cascade in determining the differential response of cervical cancer cells to anticancer drugs: an in vitro study

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Abstract

Background

Cervical cancers are usually treatable if detected in early stages by a combination of therapies. However, the prognosis of cervical cancer patients with metastasis remains unfavorable due to the fact that most of the cervical carcinomas are either resistant to anticancer drugs or show signs of relapse after initial treatment. Therefore, it is important to control the chemoresistance as it is the key to develop effective treatment options for cervical cancer.

Objective

The current study aimed at evaluating the differential responses of cervical cancer cells to anti-cancer drugs and assessed whether the differences in the expression profiles of antioxidant genes regulated by nuclear factor erythroid-2-related factor 2 (NRF2), led to the variations in the sensitivities of the cancer cells to treatment.

Methodology

Three cervical cancer cell lines were investigated for their differences in NRF2 pathway by measuring the gene expression and enzyme activity. The differences in the sensitivity to anti-cancer drugs and variation in ROS profile was also evaluated. The addition of exogenous drugs to manipulate the intracellular ROS and its effect on NRF2 pathway genes was also investigated.

Results

HeLa and SiHa cells were more sensitive to cisplatin and oxaliplatin treatment than C33A cells. HeLa and SiHa cells had significantly lower NRF2 gene levels, NQO1 enzyme activity and basal GSH levels than C33A cells. Levels of ROS induced were higher in HeLa than C33A cells.

Conclusion

Overall, the differences in the cellular levels of antioxidant regulatory genes led to the differential response of cervical cancer cells to anti-cancer drugs.

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Data availability

The data that support the findings of this study are available on request from the corresponding author.

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Acknowledgements

The authors would like to acknowledge the infrastructure support provided by the Department of Science & Technology to CEMR Laboratory (CR-FST-LS-1/2018/178) and to the Department of Biochemistry (SR/FST/LS-1-539/2012), the laboratory facilities provided by CEMR Laboratory, Department of Biochemistry, and JSS Academy of Higher Education & Research (Mysore, Karnataka, India). Pushkal Sinduvadi Ramesh (PSR) acknowledges the award of Senior Research Fellowship (08/721(0001)/2019-EMR-I) from Council of Scientific and Industrial Research (CSIR), Government of India.

Funding

No funding was received for conducting this study.

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Authors and Affiliations

  1. Centre of Excellence in Molecular Biology and Regenerative Medicine (DST-FIST Sponsored), Department of Biochemistry, JSS Medical College, JSS Academy of Higher Education and Research, Mysuru, 570015, India

    Pushkal Sinduvadi Ramesh, Suma M. Nataraj & Devananda Devegowda

  2. Department of Biochemistry, JSS Medical College, JSS Academy of Higher Education and Research, Mysuru, 570015, India

    Sharanya Raja, Shwethambari Harave Udayakumar & Shruthi Chandrashekar

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  1. Pushkal Sinduvadi Ramesh
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  2. Sharanya Raja
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  6. Devananda Devegowda
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Contributions

Conceptualization: PSR and DD; Data curation, Formal analysis, Methodology: PSR, SR, SHU, and SC; Project administration, Resources and Supervision: SMN and DD; Writing-original draft: PSR; Writing-review & editing: SMN and DD; Final approval of the manuscript: PSR, SR, SHU, SC, SMN and DD.

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Correspondence to Devananda Devegowda.

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Ramesh, P.S., Raja, S., Udayakumar, S.H. et al. Role of NRF2 cascade in determining the differential response of cervical cancer cells to anticancer drugs: an in vitro study. Mol Biol Rep 49, 109–119 (2022). https://doi.org/10.1007/s11033-021-06848-2

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