Differential effects of thapsigargin analogues on apoptosis of prostate cancer cells Complex regulation by intracellular calcium
Differential effects of thapsigargin analogues on apoptosis of prostate cancer cells Complex regulation by intracellular calcium
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DOI：
10.1111/febs.12475
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发表时间：
2013-11-01
期刊：
影响因子：
5.4
通讯作者：
Moller, Jesper V.
中科院分区：
文献类型：
--
作者：
Dubois, Charlotte;Vanden Abeele, Fabien;Moller, Jesper V.
毒胡萝卜素（Tg）和Tg-型类似物抑制肌浆网Ca 2 +-ATP酶（SERCA）被认为是通过激活凋亡途径触发细胞死亡。这些类似物中的一些在作为肽缀合的前药适当靶向癌细胞后可用作抗癌剂。考虑到这一点，本研究评估了用12-氨基十二烷酰基接头和Leu（Leu-8ADT）、天冬氨酸（Asp-8ADT）或Boc-8ADT取代的毒胡萝卜素对LNCaP雄激素敏感性癌细胞的作用。我们的研究结果表明，无论是Leu-8ADT和Asp-8ADT导致快速ER钙耗竭和跨质膜钙内流的激活存储操作的钙进入。相比之下，Boc-8ADT对ER Ca 2+的消耗是一个非常缓慢的过程，不会明显增加细胞溶质Ca 2+并激活钙库操纵的钙内流，因为该化合物对SERCA的抑制非常缓慢。然而，我们发现，Boc-8ADT是一个更有效的诱导凋亡比Tg和Leu-8ADT。与Tg和其他类似物相比，由Asp-8ADT诱导的细胞凋亡是非常温和的，尽管该化合物也激活了钙库操作的钙进入，并且在高浓度（1 M）下引起严重的形态学变化，反映了细胞活力降低。我们的结论是，许多因素需要考虑这些化合物的优化，在药物设计。在这些内质网应激诱导的Ca 2+内质网动员似乎特别重要，而早期胞质中的Ca 2+浓度增加之前的执行阶段的凋亡似乎是没有，或很少，后续的凋亡效应的后果。
The inhibition of sarcoplasmic reticulum Ca2+-ATPase (SERCA) by thapsigargin (Tg) and Tg-type analogues is considered to trigger cell death by activation of apoptotic pathways. Some of these analogues may be useful as antineoplastic agents after appropriate targeting as peptide conjugated prodrugs to cancer cells. With this in mind, this study evaluates the effect on LNCaP androgen-sensitive cancer cells of thapsigargin substituted with 12-aminododecanoyl linkers and Leu (Leu-8ADT), aspartate (Asp-8ADT) or Boc-8ADT. Our results show that both Leu-8ADT and Asp-8ADT result in rapid ER calcium depletion and an influx of calcium across the plasma membrane by activation of store-operated calcium entry. By contrast, ER Ca2+ depletion by Boc-8ADT is a very slow process that does not perceptibly increase cytosolic Ca2+ and activate store-operated calcium entry, because the inhibition of SERCA with this compound is very slow. Nevertheless, we find that Boc-8ADT is a more efficient inducer of apoptosis than both Tg and Leu-8ADT. Compared with Tg and the other analogues, apoptosis induced by Asp-8ADT is very modest, although this compound also activates store-operated calcium entry and at high concentrations (1m) causes severe morphological changes, reflecting decreased cell viability. We conclude that many factors need to be considered for optimization of these compounds in antineoplastic drug design. Among these ER stress induced by Ca2+ endoplasmic reticulum mobilization seems particularly important, whereas the early cytosolic increase of Ca2+ concentration preceding the executive phase of apoptosis appears to be of no, or little, consequence for a subsequent apoptotic effect.