NS-11021 在黑色素瘤和胰管腺癌细胞系中独立于 BK 通道调节癌症相关过程

发表日期：2022-03-10

NS-11021 Modulates Cancer-Associated Processes Independently of BK Channels in Melanoma and Pancreatic Duct Adenocarcinoma Cell Lines

Potassium channels permit the selective passage of K+ ions across the cell me brane and are important for setting the membrane potential and for the transmission of electrical signals in all cells. Ca2+ activated K+ channels provide a means to couple intracellular calcium signaling to changes of the membrane potential. Among these, the large-conductance Ca2+-activated K+ channel, known as BK, has been proposed to be involved in several cancer-associated processes. In the present work, we tested various BK channel activators for anti-cancer effects in melanoma and pancreatic duct carcinoma cell lines. Only one of the activators (NS-11021) had effects on cancer-associated processes. However, the compound, as a side-effect, also increased the intracellular Ca2+ concentration independently of BK channel activation. Overall, we conclude that the activation of the BK channel by itself is not sufficient to produce beneficial anti-cancer effects.

钾通道允许 K +离子选择性地穿过细胞膜，并且对于设置膜电位和在所有细胞中传输电信号很重要。Ca 2+激活的K +通道提供了一种将细胞内钙信号传导与膜电位变化耦合的方法。其中，大电导 Ca 2+活化的 K +通道，称为 BK，已被提议参与几个癌症相关的过程。在目前的工作中，我们测试了各种 BK 通道激活剂在黑色素瘤和胰管癌细胞系中的抗癌作用。只有一种激活剂 (NS-11021) 对癌症相关过程有影响。然而，作为副作用，该化合物还增加了细胞内 Ca 2+浓度，而与 BK 通道激活无关。总的来说，我们得出结论，BK 通道本身的激活不足以产生有益的抗癌作用。

细胞培养瓶

Potassium channels have emerged as regulators of carcinogenesis, thus introducing possible new therapeutic strategies in the fight against cancer. In particular, the large-conductance Ca2+-activated K+ channel, often referred to as BK channel, is involved in several cancer-associated processes. Here, we investigated the effects of different BK activators, NS-11021, NS-19504, and BMS-191011, in IGR39 (primary melanoma cell line) and Panc-1 (primary pancreatic duct carcinoma cell line), highly expressing the channel, and in IGR37 (metastatic melanoma cell line) that barely express BK. Our data showed that NS-11021 and NS-19504 potently activated BK channels in IGR39 and Panc-1 cells, while no effect on channel activation was detected in IGR37 cells. On the contrary, BK channel activator BMS-191011 was less effective. However, only NS-11021 showed significant effects in cancer-associated processes, such as cell survival, migration, and proliferation in these cancer cell lines. Moreover, NS-11021 led to an increase of intracellular Ca2+ concentration, independent of BK channel activation, thus complicating any interpretation of its role in the regulation of cancer-associated mechanisms. Overall, we conclude that the activation of the BK channel by itself is not sufficient to produce beneficial anti-cancer effects in the melanoma and PDAC cell lines examined. Importantly, our results raise an alarm flag regarding the use of presumably specific BK channel openers as anti-cancer agents.

钾通道已成为致癌的调节剂，因此在抗击癌症方面引入了可能的新治疗策略。特别是，大电导 Ca 2+激活的 K +通道，通常称为 BK 通道，参与多种癌症相关过程。在这里，我们研究了不同 BK 激活剂 NS-11021、NS-19504 和 BMS-191011 在 IGR39（原发性黑色素瘤细胞系）和 Panc-1（原发性胰管癌细胞系）中的作用，高表达通道，在几乎不表达 BK 的 IGR37（转移性黑色素瘤细胞系）中。我们的数据显示 NS-11021 和 NS-19504 在 IGR39 和 Panc-1 细胞中有效激活 BK 通道，而在 IGR37 细胞中未检测到对通道激活的影响。相反，BK 通道激活剂 BMS-191011 效果较差。然而，只有 NS-11021 在癌症相关过程中显示出显着效果，例如这些癌细胞系中的细胞存活、迁移和增殖。此外，NS-11021 导致细胞内 Ca2+浓度，独立于 BK 通道激活，从而使对其在调节癌症相关机制中的作用的任何解释变得复杂。总体而言，我们得出结论，BK 通道本身的激活不足以在所检查的黑色素瘤和 PDAC 细胞系中产生有益的抗癌作用。重要的是，我们的结果对使用可能特定的 BK 通道开放剂作为抗癌剂提出了警告。

细胞工厂

In the present study, we clearly demonstrated that both cancer cell lines (IGR39 and Panc-1) exhibit increased BK channel activity following treatment with BK activators (NS-11021/NS-19504), while BMS-191011 was almost ineffective. In addition, we report that NS-11021 leads to a BK-independent increase of intracellular Ca2+ concentration, thus complicating any interpretation of its role as specific BK channel activator.

Indeed, we strongly discourage the use of the presumably specific BK channel openers NS-11021 and BMS-191011 for investigation of the potential of BK channel modulation as a means to reduce cancer progression.

Employing the more specific activator NS-19504, our study revealed for the first time that KCNMA1 does not directly exhibit an oncogenic potential for analyzed cell lines. However, since the role of BK channels in human cancer is a very complex one and may not be a universal one, further studies on the function of BK channels in pathophysiological processes, such as Ca2+ entry, are needed to unmask the molecular mechanism by which BK channel could modulate events related to cancer.

In conclusion, our results raise an important alarm flag regarding the use of potential specific BK channel openers as anti-cancer agents. However, the possibility of determining the molecular or biophysical features of ionic channels can help in designing outstanding therapeutic strategies that combine the easy accessibilities of ion channel molecule with their modulation, and, hopefully, with the absence of potentially harmful side effects.

三角细胞摇瓶

在本研究中，我们清楚地证明了两种癌细胞系（IGR39 和 Panc-1）在用 BK 激活剂（NS-11021/NS-19504）处理后都表现出增加的 BK 通道活性，而 BMS-191011 几乎无效。此外，我们报告说 NS-11021 导致细胞内 Ca 2+浓度不依赖于 BK 的增加，从而使对其作为特定 BK 通道激活剂作用的任何解释变得复杂。