Lithium chloride increases sensitivity to photon irradiation treatment in primary mesenchymal colon cancer cells.

Abstract

Colorectal cancer (CRC) is the third most prevalent type of cancer worldwide. It is also the second most common cause of cancer-associated mortality; it accounted for about 9.2% of all cancer deaths in 2018, most of which were due to resistance to therapy. The main treatment for CRC is surgery, generally associated with chemotherapy, radiation therapy and combination therapy. However, while chemo-radiotherapy kills differentiated cancer cells, mesenchymal stem-like cells are resistant to this treatment, and this can give rise to therapy-resistant tumors. Our previous study isolated T88 primary colon cancer cells from a patient with sporadic colon cancer. These cells exhibited mesenchymal and epithelial features, high levels of epithelial-to-mesenchymal transition transcription factors, and stemness markers. In addition, it was revealed that lithium chloride (LiCl), a specific glycogen synthase kinase (GSK)-3β inhibitor, induced both the mesenchymal-to-epithelial transition and differentiation, and also reduced cell migration, stemness features and cell plasticity in these primary colon cancer cells. The aim of the present study was to investigate the effect of LiCl treatment on the viability of primary colon cancer cells exposed to 7 Gy delivered by high-energy photon beams, which corresponds to 6 megavolts of energy. To achieve this aim, the viability of irradiated T88 cells was compared with that of irradiated T88 cells pre-treated with LiCl. As expected, it was observed that LiCl sensitized primary colon cancer cells to high-energy photon irradiation treatment. Notably, the decrease in cell viability was greater with combined therapy than with irradiation alone. To explore the molecular basis of this response, the effect of LiCl on the expression of Bax, p53 and Survivin, which are proteins involved in the apoptotic mechanism and in death escape, was analyzed. The present study revealed that LiCl upregulated the expression of pro-apoptotic proteins and downregulated the expression of proteins involved in survival. These effects were enhanced by high-energy photon irradiation, suggesting that LiCl could be used to sensitize colon cancer cells to radiation therapy.