Inhibition of polyamine biosynthesis by DFMO reverts partially Ca2+ remodeling in colon cancer cells

Abstract

Recently we have shown that colon cancer cells undergo remodeling of intracellular Ca2+ homeostasis including changes in store-operated Ca2+ entry (SOCE), store-operated currents and Ca2+ store content associated to changes in molecular players involved in SOCE (Sobradillo et al., 2014). Reversing this remodeling could contribute to protection against cancer and cancer chemoprevention. Difluoromethylornithine (DFMO) or Eflornithine is a suicide inhibitor of ornithine decarboxylase (ODC), the limiting step in the synthesis of polyamines that is considered one of the best chemopreventive compounds against colon cancer. Here we tested the effects of DFMO treatment on SOCE, SOCs, Ca2+ store content, the molecular players involved and resistance to cell death, a critical cancer hallmark. We found that ODC was largely overexpressed in colon cancer cells suggesting increased synthesis of polyamines in colon cancer cells. Short-term treatment with DFMO (500 µM, 12 h) decreased significantly SOCE and store-operated currents in colon cancer cells. DFMO had no effect on Icrac but prevented selectively the appearance of the outward component of store-operated current likely mediated by TRPC1. DFMO also increased Ca2+ store content and the fraction of cells undergoing early apoptosis induced by H2O2. At the molecular level, we found DFMO tend to decrease all molecular players involved in SOCE except Stim2 but the effects were statistically significant only for TRPC1 mRNA. In summary, inhibition of polyamine synthesis decreases SOCE and SOCs in human colon cancer cells acting probably on expression of TRPC1 and tends to increase Ca2+ store content and susceptibility to apoptosis in human colon cancer cells. Thus, reverting partially Ca2+ remodeling in colon cancer cells and likely contributing to colon cancer chemoprevention.