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Carbon ion beam triggers both caspase-dependent and caspase-independent pathway of apoptosis in HeLa and status of PARP-1 controls intensity of apoptosis

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Abstract

High linear energy transfer (LET) carbon ion beam (CIB) is becoming very promising tool for various cancer treatments and is more efficient than conventional low LET gamma or X-rays to kill malignant or radio-resistant cells, although detailed mechanism of cell death is still unknown. Poly (ADP-ribose) polymerase-1 (PARP-1) is a key player in DNA repair and its inhibitors are well-known as radio-sensitizer for low LET radiation. The objective of our study was to find mechanism(s) of induction of apoptosis by CIB and role of PARP-1 in CIB-induced apoptosis. We observed overall higher apoptosis in PARP-1 knocked down HeLa cells (HsiI) compared with negative control H-vector cells after irradiation with CIB (0–4 Gy). CIB activated both intrinsic and extrinsic pathways of apoptosis via caspase-9 and caspase-8 activation respectively, followed by caspase-3 activation, apoptotic body, nucleosomal ladder formation and sub-G1 accumulation. Apoptosis inducing factor translocation into nucleus in H-vector but not in HsiI cells after CIB irradiation contributed caspase-independent apoptosis. Higher p53 expression was observed in HsiI cells compared with H-vector after exposure with CIB. Notably, we observed about 37 % fall of mitochondrial membrane potential, activation of caspase-9 and caspase-3 and mild activation of caspase-8 without any detectable apoptotic body formation in un-irradiated HsiI cells. We conclude that reduction of PARP-1 expression activates apoptotic signals via intrinsic and extrinsic pathways in un-irradiated cells. CIB irradiation further intensified both intrinsic and extrinsic pathways of apoptosis synergistically along with up-regulation of p53 in HsiI cells resulting overall higher apoptosis in HsiI than H-vector.

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Abbreviations

AIF:

Apoptosis inducing factor

CIB:

Carbon ion beam 19

DAPI:

4′, 6-Diamidino-2-phenylindole

DCFH/DA:

2′,7′-Dichlorofluorescin diacetate

FACS:

Fluorescence activated cell sorter

FITC:

Fluorescein isothiocyanate

IF:

Immunofluorescence

LET:

Linear energy transfer

MMP:

Mitochondrial membrane potential

PARP-1:

Poly (ADP-ribose) polymerase-1

PI:

Propidium iodide

Rhd:

Rhodamine

SD:

Standard deviation

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Acknowledgments

UG thanks Inter-University Accelerator Centre (IUAC), New Delhi for financial support as well as for availing instrumental facility. UG is grateful to Department of Science & Technology (DST), Govt. of India for providing infrastructural facility in Department of Biochemistry & Biophysics, University of Kalyani under DST-FIST program. UG thanks DST for partial fulfillment of financial support under project SR/SO/BB-0017. AG is grateful to Indian Council of Medical Research (ICMR), New Delhi for senior research fellowship. AG also acknowledges his gratitude to Dr. Geetanjali Pujari, Young Scientist (DST First Track Scheme), IUAC, New Delhi for her help during the irradiation of samples.

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The authors declare that there are no conflicts of interest regarding the publication of this paper.

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Authors and Affiliations

  1. Department of Biochemistry & Biophysics, University of Kalyani, Kalyani, 741235, India

    Atanu Ghorai & Utpal Ghosh

  2. Inter-University Accelerator Center (IUAC), Aruna Asaf Ali Marg, New Delhi, 110067, India

    Asitikantha Sarma

  3. Crystallography and Molecular Biology Division, Saha Institute of Nuclear Physics, 1/AF Bidhannagar, Kolkata, 700 064, India

    Nitai P. Bhattacharyya

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  1. Atanu Ghorai
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Ghorai, A., Sarma, A., Bhattacharyya, N.P. et al. Carbon ion beam triggers both caspase-dependent and caspase-independent pathway of apoptosis in HeLa and status of PARP-1 controls intensity of apoptosis. Apoptosis 20, 562–580 (2015). https://doi.org/10.1007/s10495-015-1107-3

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