S-Adenosyl-l-Methionine: a strategy for overcoming uL3-mediated drug resistance in p53 deleted colon cancer cells

In the field of anticancer therapy, re-sensitizing tumor cells to the drugs by exploiting novel strategies is a promising approach to overcome the drug resistance with consequent improvement in clinical treatment. In this context, to investigate novel therapeutic approaches taking advantage from anticancer and antiproliferative effects of natural compounds, we focused our attention on S-adenosyl-L-methionine (AdoMet), a ubiquitous and naturally occurring sulfonium compound. We tested its potential in overcoming chemoresistance observed in our model of colon cancer cells lacking functional p53 and characterized by low expression levels of uL3[1,2]. Here, we demonstrated that AdoMet exerts its cytotoxic activity in these cells and, more importantly, restores their sensitivity to 5-fluorouracil (5-FU) treatment. In particular, AdoMet exposure impairs cell cycle progression inducing cell cycle arrest at the S phase, which was associated with a significant increase of Cyclin E and a decrease of Cyclin D. Furthermore, AdoMet inhibits autophagy, increases the production of reactive oxygen species, and finally activates the caspase cascade, triggering the apoptotic pathway. To best of our knowledge, the present study unveils, for the first time, the capability of AdoMet to resensitize drug resistant colon cancer cells indicating this natural compound as a potential therapeutic agent for colon cancer cells showing p53 and uL3 lower levels. [1] A. Pecoraro, P. Carotenuto, G. Russo, A. Russo. Sci Rep. (2019), 9, 15431. [2] A. Pecoraro, P. Carotenuto, B. Franco, R. De Cegli, G. Russo, A. Russo. Int J Mol Sci. (2020), 21, 2143.