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

NS-11021 在黑色素瘤和胰管腺癌細胞系中獨立于 BK 通道調(diào)節(jié)癌癥相關(guān)過程

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.

鉀通道允許 K +離子選擇性地穿過細胞膜，并且對于設(shè)置膜電位和在所有細胞中傳輸電信號很重要。Ca 2+激活的K +通道提供了一種將細胞內(nèi)鈣信號傳導(dǎo)與膜電位變化耦合的方法。其中，大電導(dǎo) Ca 2+活化的 K +通道，稱為 BK，已被提議參與幾個癌癥相關(guān)的過程。在目前的工作中，我們測試了各種 BK 通道激活劑在黑色素瘤和胰管癌細胞系中的抗癌作用。只有一種激活劑 (NS-11021) 對癌癥相關(guān)過程有影響。然而，作為副作用，該化合物還增加了細胞內(nèi) Ca 2+濃度，而與 BK 通道激活無關(guān)?？偟膩碚f，我們得出結(jié)論，BK 通道本身的激活不足以產(chǎn)生有益的抗癌作用。

細胞培養(yǎng)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.

鉀通道已成為致癌的調(diào)節(jié)劑，因此在抗擊癌癥方面引入了可能的新治療策略。特別是，大電導(dǎo) Ca 2+激活的 K +通道，通常稱為 BK 通道，參與多種癌癥相關(guān)過程。在這里，我們研究了不同 BK 激活劑 NS-11021、NS-19504 和 BMS-191011 在 IGR39（原發(fā)性黑色素瘤細胞系）和 Panc-1（原發(fā)性胰管癌細胞系）中的作用，高表達通道，在幾乎不表達 BK 的 IGR37（轉(zhuǎn)移性黑色素瘤細胞系）中。我們的數(shù)據(jù)顯示 NS-11021 和 NS-19504 在 IGR39 和 Panc-1 細胞中有效激活 BK 通道，而在 IGR37 細胞中未檢測到對通道激活的影響。相反，BK 通道激活劑 BMS-191011 效果較差。然而，只有 NS-11021 在癌癥相關(guān)過程中顯示出顯著效果，例如這些癌細胞系中的細胞存活、遷移和增殖。此外，NS-11021 導(dǎo)致細胞內(nèi) Ca2+濃度，獨立于 BK 通道激活，從而使對其在調(diào)節(jié)癌癥相關(guān)機制中的作用的任何解釋變得復(fù)雜?？傮w而言，我們得出結(jié)論，BK 通道本身的激活不足以在所檢查的黑色素瘤和 PDAC 細胞系中產(chǎn)生有益的抗癌作用。重要的是，我們的結(jié)果對使用可能特定的 BK 通道開放劑作為抗癌劑提出了警告。

細胞工廠

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.

三角細胞搖瓶

在本研究中，我們清楚地證明了兩種癌細胞系（IGR39 和 Panc-1）在用 BK 激活劑（NS-11021/NS-19504）處理后都表現(xiàn)出增加的 BK 通道活性，而 BMS-191011 幾乎無效。此外，我們報告說 NS-11021 導(dǎo)致細胞內(nèi) Ca 2+濃度不依賴于 BK 的增加，從而使對其作為特定 BK 通道激活劑作用的任何解釋變得復(fù)雜。

事實上，我們強烈反對使用可能特定的 BK 通道開放劑 NS-11021 和 BMS-191011 來研究 BK 通道調(diào)節(jié)作為減少癌癥進展的手段的潛力。

使用更具體的激活劑 NS-19504，我們的研究首次揭示KCNMA1對分析的細胞系沒有直接表現(xiàn)出致癌潛力。然而，由于BK通道在人類癌癥中的作用非常復(fù)雜，可能不是普遍的，因此需要進一步研究BK通道在Ca 2+進入等病理生理過程中的作用，以揭示其分子機制。 BK 通道可以調(diào)節(jié)與癌癥相關(guān)的事件。

總之，我們的結(jié)果對使用潛在的特異性 BK 通道開放劑作為抗癌劑提出了重要的警告。然而，確定離子通道的分子或生物物理特征的可能性有助于設(shè)計出色的治療策略，將離子通道分子的易接近性與其調(diào)節(jié)相結(jié)合，并且希望沒有潛在的有害副作用。

關(guān)鍵詞： BK頻道,BK 開瓶器,鈣,IGR39 細胞,Panc-1細胞,癌癥,BK channel,BK openers,calcium, IGR39 cells, Panc-1 cells,cancers

來源：MDPI  https://www.mdpi.com/2072-6694/13/23/6144