Cytoproliferative effect of low dose alpha radiation in human lung cancer cells is associated with connexin 43, caveolin-1, and survivin pathway

Abstract

Purpose

High LET including alpha radiation-based approaches have been proved as a promising mode for cancer therapy owing to their biophysical and radiobiological advantages compared to photon beams. Studies pertaining to effect of α-radiation on cancer cells are limited to cytotoxic high doses.

Materials and methods

In this study, human lung adenocarcinoma (A549) cells were α-irradiated using ²⁴¹Am α-irradiator and effects of low dose of alpha radiation on these cells was studied under in vitro and in vivo conditions.

Results

Clonogenic and other assays showed increased cellular proliferation at lower doses (1.36 and 6.8 cGy) but killing at higher doses (13.6–54.4 cGy). Further studies at low dose of alpha (1.36 cGy) showed increased TGF-β1 in the conditioned medium (CM) at early time point (24 h) but CM replacement did not affect the clonogenic survival. In these cells, increased phosphorylation of connexin 43 was correlated with decrease in gap-junction communication observed by dye transfer co-culture experiment. A decrease in caveolin-1 but increase in survivin expression was observed in low dose α-irradiated cells. An increase in cyclinD1 and decrease in Bcl-2, the target proteins of survivin, was observed in these cells. Low dose α-irradiated cancer cells transplanted in SCID mice showed significantly higher tumor volume, which was accompanied with an increased fraction of mitotic and PCNA/Ki67 positive cells in these tumor tissues.

Conclusions

Taken together, our results suggest an increase in proliferation and tumor volume at in vitro and in vivo levels, respectively, when A549 cells were irradiated with low dose of α-radiation. These findings may be relevant for a better understanding of radiobiological processes during high LET-based cancer radiotherapy.

Keywords:

• Alpha radiation
• cell proliferation
• lung cancer cells
• low dose radiation
• survival

Acknowledgments

Authors acknowledge the technical assistance of Prayag Amin and Deepika Bhange for flow cytometry and animal experiments, respectively.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

Bhabha Atomic Research Center, Department of Atomic Energy, Government of India.

Notes on contributors

Vasumathy Rajan

R. Vasumathy, M.Sc. is a Scientific Assistant in Radiation Biology & Health Sciences Division, Bhabha Atomic Research Center, Mumbai, India.

Badri Narain Pandey

Dr. Badri Narain Pandey, Ph.D. is a Scientist at Radiation Biology & Health Sciences Division, Bhabha Atomic Research Center, Mumbai, Professor, Homi Bhabha National Institute (HNBI), Mumbai, India and a Fellow of Association of International Union Against Cancer Control (UICC) Fellows, Switzerland.