Polyamine stimulation perturbs intracellular Ca2+ homeostasis and decreases viability of breast cancer BT474 cells

Abstract Intracellular polyamines such as spermine and spermidine are essential to cell growth in normal and especially in cancer cells. However, whether extracellular polyamines affect cancer cell survival is unknown. We therefore examined the actions of extracellular polyamines on breast cancer BT474 cells. Our data showed that spermine, spermidine, and putrescine decreased cell viability by apoptosis. These polyamines also elicited Ca 2+ signals, but the latter were unlikely triggered via Ca 2+ -sensing receptor (CaSR) as BT474 cells have been demonstrated previously to lack CaSR expression. Spermine-elicited Ca 2+ response composed of both Ca 2+ release and Ca 2+ influx. Spermine caused a complete discharge of the cyclopiazonic acid (CPA)-sensitive Ca 2+ pool and, expectedly, endoplasmic reticulum (ER) stress. The Ca 2+ influx pore opened by spermine was Mn 2+ -impermeable, distinct from the CPA-triggered store-operated Ca 2+ channel, which was Mn 2+ -permeable. Spermine cytotoxic effects were not due to oxidative stress, as spermine did not trigger reactive oxygen species formation. Our results therefore suggest that spermine acted on a putative polyamine receptor in BT474 cells, causing cytotoxicity by Ca 2+ overload, Ca 2+ store depletion, and ER stress.