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 Ca2+ signals, but the latter were unlikely triggered via Ca2+-sensing receptor (CaSR) as BT474 cells have been demonstrated previously to lack CaSR expression. Spermine-elicited Ca2+ response composed of both Ca2+ release and Ca2+ influx. Spermine caused a complete discharge of the cyclopiazonic acid (CPA)-sensitive Ca2+ pool and, expectedly, endoplasmic reticulum (ER) stress. The Ca2+ influx pore opened by spermine was Mn2+-impermeable, distinct from the CPA-triggered store-operated Ca2+ channel, which was Mn2+-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 Ca2+ overload, Ca2+ store depletion, and ER stress.

中文翻译：

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多胺刺激扰乱细胞内 Ca2+ 稳态并降低乳腺癌 BT474 细胞的活力

摘要 细胞内多胺如精胺和亚精胺对正常细胞尤其是癌细胞的细胞生长至关重要。然而，细胞外多胺是否影响癌细胞存活尚不清楚。因此，我们检查了细胞外多胺对乳腺癌 BT474 细胞的作用。我们的数据显示精胺、亚精胺和腐胺通过细胞凋亡降低细胞活力。这些多胺也引发 Ca2+ 信号，但后者不太可能通过 Ca2+ 感应受体 (CaSR) 触发，因为先前已证明 BT474 细胞缺乏 CaSR 表达。精胺引发的 Ca2+ 反应由 Ca2+ 释放和 Ca2+ 流入组成。精胺导致环吡氮酸 (CPA) 敏感的 Ca2+ 池完全释放，并且预期会导致内质网 (ER) 应激。精胺打开的 Ca2+ 流入孔是 Mn2+ 不可渗透的，不同于 CPA 触发的存储操作的 Ca2+ 通道，后者是 Mn2+ 可渗透的。精胺的细胞毒性作用不是由于氧化应激，因为精胺不会触发活性氧的形成。因此，我们的结果表明，精胺作用于 BT474 细胞中推定的多胺受体，通过 Ca2+ 超载、Ca2+ 储存耗竭和 ER 应激引起细胞毒性。