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Profilin potentiates chemotherapeutic agents mediated cell death via suppression of NF-κB and upregulation of p53

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Abstract

The molecular mechanism by which Profilin acts as a tumor suppressor is still unclear. Several chemotherapeutic agents, used till date either have unfavorable side effects or acquired resistance in tumor cells. Our findings show that Profilin enhances cell death mediated by several chemotherapeutic-agents. The activation of NF-κB and its dependent genes, mediated by paclitaxel and vinblastine, was completely inhibited in Profilin overexpressing cells. This inhibition was due to the Profilin mediated attenuation of IκBα degradation, thereby preventing p65 nuclear translocation and low NF-κB DNA binding activity.Moreover, Profilin increases level of p53 in the presence of known inducers, such as doxorubicin, vinblastine, and benzofuran. This increased p53 level leads to enhanced cell death as indicated by activation of caspases 3, 8, 9, which results in cleavage of PARP.Furthermore, knocking down of p53 in Profilin overexpressing cells leads to decreased cell death. Ectopic expression of Profilin in HCT116 p53 knock out cells showed lesser cell death as compared to the HCT116 p53 wild type cells. For the first time, we provide evidences, which suggest that Profilin synergizes with chemotherapeutic drugs to induce tumor cell death by regulating NF-κB and p53. Thus, modulation of Profilin may be a useful strategy for effective combination therapy.

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Abbreviations

ANG1:

Angiopoietin-1

AraC:

Arabinoside C

ATRA:

All-trans retinoic acid

DAPI:

4′,6-Diamidino-2-phenylindole

ICAM:

Intercellular cell adhesion molecule

IL:

Interleukin

Mdm2:

Mouse double minute 2 homolog

MTT:

3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide

NF-κb:

Nuclear transcription factor kappa B

PARP:

Poly-ADP ribose polymerase

Sp1:

Specificity protein 1

VEGF:

Vascular endothelial growth factor

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Acknowledgments

This work was supported by the core grant of Centre for DNA Fingerprinting and Diagnostics (CDFD). We thank Council for Scientific and Industrial Research (CSIR), Department of Biotechnology (DBT) and University Grants Commission (UGC), Govt. of India for providing fellowships to AZ, RBM, and PG, respectively.

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Authors and Affiliations

  1. Laboratory of Immunology, Centre for DNA Fingerprinting & Diagnostics, Nampally, Hyderabad, Telangana, 500 001, India

    Adeel H. Zaidi, Nune Raviprakash, Raveendra B. Mokhamatam, Pankaj Gupta & Sunil K. Manna

  2. Graduate Studies, Manipal University, Manipal, Karnataka, 576104, India

    Adeel H. Zaidi, Raveendra B. Mokhamatam & Pankaj Gupta

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  1. Adeel H. Zaidi
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  2. Nune Raviprakash
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Correspondence to Sunil K. Manna.

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Zaidi, A.H., Raviprakash, N., Mokhamatam, R.B. et al. Profilin potentiates chemotherapeutic agents mediated cell death via suppression of NF-κB and upregulation of p53. Apoptosis 21, 502–513 (2016). https://doi.org/10.1007/s10495-016-1222-9

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