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Increased expression of Profilin potentiates chemotherapeutic agent-mediated tumour regression

British Journal of Cancer volume 126, pages 1410–1420 (2022)Cite this article

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Abstract

Background

Targeted cancer therapy is an alternative to standard chemotherapy for a better prognosis. Although its incompetency for triple-negative breast cancer (TNBC), treatment still relies on classical chemotherapy. Increasing evidence suggest that chemotherapeutic drug-induced toxic effect could be minimised by combinatorial therapy. Profilin’s familiar anti-tumorigenic activity can be utilised in combination with the drug to improve efficacy, which could be promising therapeutics to treat TNBC.

Methods

All-trans retinoic acid (ATRA) in combination with vinblastine was tested on human MDA MB-231 cell line (MB-231) (in vitro) and MB-231 borne breast cancer in nude mice (in vivo). Effects of combination treatment on tumour growth inhibition and apoptosis were examined by tumour volume, histology and PARP cleavage. ATRA-induced transcriptional regulation of profilin had been evaluated by gel-shift and reporter gene assays. Profilin’s role in ATRA-induced vinblastine efficacy was validated in profilin-stable and profilin-silenced cells.

Results

ATRA binds with RAR/RXR to increase the profilin expression that potentiated cell death by chemotherapeutics. ATRA priming led to vinblastine-mediated potentiation of G2–M phase cell cycle arrest in MB-231 cells and regression of breast cancer in xenograft mice at very low concentration without any adverse effects. Moreover, increased p53 and PTEN but downregulated p65 in the tumour tissues further supported the involvement of profilin for tumour regression.

Conclusions

Vinblastine at very low concentration (20 times lesser than the recommended dose for breast cancer therapeutic) significantly regress tumour growth in ATRA-primed mice without any toxic effects suggesting potential combinatorial therapeutics for TNBC.

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Fig. 1: Profilin increases chemotherapeutic agents-mediated cell death.
Fig. 2: ATRA potentiates chemotherapeutic drugs-mediated cell death through profilin upregulation.
Fig. 3: ATRA-induced profilin potentiates vinblastine-mediated G2–M arrest.
Fig. 4: ATRA induces profilin expression through RAR/RXR transcription factors binding on RARE sequence.
Fig. 5: Combinatorial treatment of ATRA and vinblastine reduces the growth of tumour xenograft in nude mice without any side effects.
Fig. 6: Combinatorial treatment of ATRA and vinblastine increases profilin, p53, PTEN and reduces p65 in tumour.

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Data availability

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

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Acknowledgements

We thank CDFDs’ Animal House Facility and Sophisticated Equipment Facility (SEF) for their support in this study.

Funding

This work was partially supported by the core grant of Centre for DNA Fingerprinting and Diagnostics (CDFD). We thank Department of Biotechnology (DBT), Govt. of India for providing fellowship to SS and the fund from DBT-NER grant.

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Authors and Affiliations

  1. Laboratory of Immunology, Centre for DNA Fingerprinting & Diagnostics, Uppal, Hyderabad, Telangana, 500 039, India

    Shashank Saurav & Sunil Kumar Manna

  2. Graduate Studies, Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India

    Shashank Saurav

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  1. Shashank Saurav
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SS performed all the experiments, data curation, investigation, analysis, manuscript writing and SKM conceptualised the project, supervised and wrote the manuscript.

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Correspondence to Sunil Kumar Manna.

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Saurav, S., Manna, S.K. Increased expression of Profilin potentiates chemotherapeutic agent-mediated tumour regression. Br J Cancer 126, 1410–1420 (2022). https://doi.org/10.1038/s41416-021-01683-5

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