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Protein kinases orchestrate cell cycle regulators in differentiating BeWo choriocarcinoma cells

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Abstract

Choriocarcinoma, a trophoblastic neoplasia, occurs in women as an incidence of abnormal pregnancy. BeWo choriocarcinoma cells derived from the abnormal placentation are a suitable model system to study the factors associated with differentiation, invasion and other cellular events as an alternative to clinical samples. Many protein kinases orchestrate the complex events of cell cycle and in case of malignancy such regulators are found to be mutated. In the present study, BeWo cells treated with forskolin (Fo) and phorbol 12-myristate 13-acetate (PMA) were used to study the role of PKA (protein kinase A) and PKC (protein kinase C), respectively, on the expression pattern of differentiation-related genes, membrane markers, PKC isoforms and cell cycle regulators. The effect of Fo and PMA on the cell proliferation was assessed. Progressive induction of alkaline phosphatase level and formation of multinucleated differentiated cells were observed in the cells treated with Fo. Exposure of cells to Fo and PMA induced the mRNA transcripts of α-hCG, β-hCG and endoglin and down-regulates E-cadherin at mRNA and protein levels. Synergistic levels of both up- and down-regulated genes/proteins were observed when cells were treated with the combination of Fo and PMA. The mRNA levels of cyclin D1, cyclin E1, p21, Rb, p53, caspase-3 and caspase-8 decreased gradually during differentiation. Fo significantly inhibited the protein levels of PCNA, Rb, PKC-α and PMA stimulated mRNA expression of PKC-ε and PKC-δ. Further, failure in the activation of essential components of the cell cycle machinery caused G2/M phase arrest in differentiating BeWo cells.

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Acknowledgements

The authors wish to express their gratitude to the Department of Science and Technology-PURSE [SR/59/Z-23/2010/38(c)] and University Grants Commission-CPEPA [8-2/2008(NS/PE)], Govt. of India for providing financial support. They also wish to express their gratitude to the Department of Microbiology and Biotechnology, Bangalore University, Bengaluru for providing the DST-FIST, UGC-SAP and laboratory facility. They wish to thank Prof. P. Kondaiah, Dept. of MRDG, IISc, Bengaluru for providing the flow cytometry facility. The author Naveen Kumar M., thank Prof. M. V. V. Subramanyam and Late E. Vijayalakshmi for their support during his research and greatly acknowledges the Council for Scientific and Industrial Research (CSIR), Govt. of India for the award of Senior Research Fellowship (09/039 (0116)/2016 EMR-I).

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  1. Rajeshwari H. Patil

    Present address: Department of Molecular Reproduction, Development and Genetics, Indian Institute of Science, Bengaluru, 560 012, Karnataka, India

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  1. Department of Microbiology and Biotechnology, Bangalore University, Jnana Bharathi Campus, Bengaluru, 560 056, Karnataka, India

    M. Naveen Kumar, Rajeshwari H. Patil, K. M. Kiran Kumar, Shubha M. Hegde, Rashmi Nagesh, K. Kavya, S. Chidananda Sharma & C. Srinivas

  2. Department of Bioinformatics and Biotechnology, Akkamahadevi Women’s University, Jnanashakthi Campus, Vijayapura, 586 108, Karnataka, India

    R. L. Babu

  3. Department of Biology and Center for Biotechnology and Biomedical Sciences, Norfolk State University, Norfolk, VA, USA

    R. L. Babu & Govindarajan T. Ramesh

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Naveen Kumar, M., Babu, R.L., Patil, R.H. et al. Protein kinases orchestrate cell cycle regulators in differentiating BeWo choriocarcinoma cells. Mol Cell Biochem 452, 1–15 (2019). https://doi.org/10.1007/s11010-018-3407-8

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