Sansone Clementina, Braca Alessandra, Ercolesi Elena, Romano Giovanna, Palumbo Anna, Casotti Raffaella, Francone Maria, Ianora Adrianna
Stazione Zoologica Anton Dohrn, Naples, Italy.
PLoS One. 2014 Jul 3;9(7):e101220. doi: 10.1371/journal.pone.0101220. eCollection 2014.
Diatoms are an important class of unicellular algae that produce bioactive polyunsaturated aldehydes (PUAs) that induce abortions or malformations in the offspring of invertebrates exposed to them during gestation. Here we compare the effects of the PUAs 2-trans,4-trans-decadienal (DD), 2-trans,4-trans-octadienal (OD) and 2-trans,4-trans-heptadienal (HD) on the adenocarcinoma cell lines lung A549 and colon COLO 205, and the normal lung/brunch epithelial BEAS-2B cell line. Using the viability MTT/Trypan blue assays, we show that PUAs have a toxic effect on both A549 and COLO 205 tumor cells but not BEAS-2B normal cells. DD was the strongest of the three PUAs tested, at all time-intervals considered, but HD was as strong as DD after 48 h. OD was the least active of the three PUAs. The effect of the three PUAs was somewhat stronger for A549 cells. We therefore studied the death signaling pathway activated in A549 showing that cells treated with DD activated Tumor Necrosis Factor Receptor 1 (TNFR1) and Fas Associated Death Domain (FADD) leading to necroptosis via caspase-3 without activating the survival pathway Receptor-Interacting Protein (RIP). The TNFR1/FADD/caspase pathway was also observed with OD, but only after 48 h. This was the only PUA that activated RIP, consistent with the finding that OD causes less damage to the cell compared to DD and HD. In contrast, cells treated with HD activated the Fas/FADD/caspase pathway. This is the first report that PUAs activate an extrinsic apoptotic machinery in contrast to other anticancer drugs that promote an intrinsic death pathway, without affecting the viability of normal cells from the same tissue type. These findings have interesting implications also from the ecological viewpoint considering that HD is one of the most common PUAs produced by diatoms.
硅藻是一类重要的单细胞藻类，能产生具有生物活性的多不饱和醛（PUAs），这些物质会导致在妊娠期接触过它们的无脊椎动物后代出现流产或畸形。在此，我们比较了多不饱和醛2-反式，4-反式-癸二烯醛（DD）、2-反式，4-反式-辛二烯醛（OD）和2-反式，4-反式-庚二烯醛（HD）对肺癌A549细胞系、结肠癌COLO 205细胞系以及正常肺/支气管上皮BEAS-2B细胞系的影响。通过活力MTT/台盼蓝检测，我们发现多不饱和醛对A549和COLO 205肿瘤细胞均有毒性作用，但对BEAS-2B正常细胞无毒性作用。在所考虑的所有时间间隔内，DD是三种受试多不饱和醛中作用最强的，但48小时后HD的作用强度与DD相当。OD是三种多不饱和醛中活性最低的。这三种多不饱和醛对A549细胞的作用稍强一些。因此，我们研究了A549细胞中激活的死亡信号通路，结果表明用DD处理的细胞激活了肿瘤坏死因子受体1（TNFR1）和Fas相关死亡结构域（FADD），通过半胱天冬酶-3导致坏死性凋亡，而未激活存活通路受体相互作用蛋白（RIP）。用OD处理细胞时也观察到了TNFR1/FADD/半胱天冬酶通路，但仅在48小时后出现。这是唯一激活RIP的多不饱和醛，这与OD相比DD和HD对细胞造成的损伤较小这一发现一致。相比之下，用HD处理的细胞激活了Fas/FADD/半胱天冬酶通路。这是首份关于多不饱和醛激活外源性凋亡机制的报告，与其他促进内源性死亡途径的抗癌药物不同，多不饱和醛不影响相同组织类型正常细胞的活力。从生态学角度来看，这些发现也具有有趣的意义，因为HD是硅藻产生的最常见的多不饱和醛之一。
