Elevation of Cytoplasmic Calcium Suppresses Microtentacle Formation and Function in Breast Tumor Cells.
Elevation of Cytoplasmic Calcium Suppresses Microtentacle Formation and Function in Breast Tumor Cells.
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钙是一种多功能和普遍存在的信号分子，长期失调可以增加癌症向身体各部位的扩散，但短期影响尚未得到充分研究。在循环中扩散的癌细胞有明显的延伸或突起，称为微触角，增强了它们附着在表面或其他细胞上的能力。在这项研究中，我们发现，在分离和悬浮的环境中，离子霉素和Thapsigargin化合物快速增加细胞钙会降低癌细胞的微趋化频率和聚集功能。急性钙诱导的信号事件促进了肌动蛋白收缩和重排的变化，负责抑制微触手。这项研究的结果支持Thapsigargin衍生物的临床试验数据，表明Ca 2+调节疗法可能用于促进自由漂浮肿瘤细胞的细胞形状和结构变化，以减少转移。循环肿瘤细胞（CTC）中的细胞骨架重塑促进转移扩散。以前的肿瘤学研究检查持续的异常钙（Ca 2+）信号和细胞骨架重塑仔细检查长期表型，如肿瘤发生和转移。肿瘤细胞中几秒到几分钟内发生的急性Ca 2+信号传导的重要性被忽视了。本研究探讨了悬浮细胞中肌动蛋白和微管蛋白细胞骨架重排和转移性微张力（McTN）表型的快速胞浆Ca 2+升高。化合物离子霉素和毒胡萝卜素急剧增加细胞质Ca 2+，抑制转移性乳腺癌细胞系MDA-MB-231和MDA-MB-436中的McTN。在治疗的第一个24小时内，McTN介导的再附着和细胞聚集的功能性降低不归因于细胞毒性。快速的细胞质Ca 2+升高与Ca 2+诱导的肌动蛋白皮质收缩和重排通过肌球蛋白轻链2和cofilin活性，而肌动蛋白聚合与Latrunculin A逆转Ca 2+介导的McTN抑制的抑制。临床前和1期和2期临床试验数据已确定毒胡萝卜素衍生物作为细胞毒性抗癌剂。这项研究的结果表明，这些化合物起作用的另一种分子机制，并且原理验证的Ca 2+调节化合物可以快速诱导自由漂浮的肿瘤细胞的形态学变化，以减少转移表型。
Calcium is a versatile and ubiquitous signaling molecule that long-term dysregulation can increase the spread of cancer to various parts of the body but that short-term effects are understudied. Disseminated cancer cells in circulation have distinct extensions or protrusions, called microtentacles, that enhance their ability to attach to surfaces or other cells. In this study, we show rapidly increasing cellular calcium with the compounds of Ionomycin and Thapsigargin decreases the microtentacle frequency and clustering functions on cancer cells in a detached and suspended environment. Acute calcium-induced signaling events promoted changes to actin contraction and rearrangement responsible for suppressing microtentacles. The results from this study support clinical trial data from Thapsigargin derivatives, suggesting Ca2+ modulating therapies can potentially be used to promote cellular shape and structure changes in free-floating tumor cells to reduce metastasis. Cytoskeletal remodeling in circulating tumor cells (CTCs) facilitates metastatic spread. Previous oncology studies examine sustained aberrant calcium (Ca2+) signaling and cytoskeletal remodeling scrutinizing long-term phenotypes such as tumorigenesis and metastasis. The significance of acute Ca2+ signaling in tumor cells that occur within seconds to minutes is overlooked. This study investigates rapid cytoplasmic Ca2+ elevation in suspended cells on actin and tubulin cytoskeletal rearrangements and the metastatic microtentacle (McTN) phenotype. The compounds Ionomycin and Thapsigargin acutely increase cytoplasmic Ca2+, suppressing McTNs in the metastatic breast cancer cell lines MDA-MB-231 and MDA-MB-436. Functional decreases in McTN-mediated reattachment and cell clustering during the first 24 h of treatment are not attributed to cytotoxicity. Rapid cytoplasmic Ca2+ elevation was correlated to Ca2+-induced actin cortex contraction and rearrangement via myosin light chain 2 and cofilin activity, while the inhibition of actin polymerization with Latrunculin A reversed Ca2+-mediated McTN suppression. Preclinical and phase 1 and 2 clinical trial data have established Thapsigargin derivatives as cytotoxic anticancer agents. The results from this study suggest an alternative molecular mechanism by which these compounds act, and proof-of-principle Ca2+-modulating compounds can rapidly induce morphological changes in free-floating tumor cells to reduce metastatic phenotypes.
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影响因子：
4.2
作者：
Aseervatham J
通讯作者：
Aseervatham J
影响因子：
4.6
作者：
Bhandary L;Bailey PC;Chang KT;Underwood KF;Lee CJ;Whipple RA;Jewell CM;Ory E;Thompson KN;Ju JA;Mathias TM;Pratt SJP;Vitolo MI;Martin SS
通讯作者：
Martin SS
影响因子：
5.6
作者：
Azimi I;Robitaille M;Armitage K;So CL;Milevskiy MJG;Northwood K;Lim HF;Thompson EW;Roberts-Thomson SJ;Monteith GR
通讯作者：
Monteith GR
影响因子：
11.2
作者：
Boggs AE;Vitolo MI;Whipple RA;Charpentier MS;Goloubeva OG;Ioffe OB;Tuttle KC;Slovic J;Lu Y;Mills GB;Martin SS
通讯作者：
Martin SS
影响因子：
4.8
作者：
Bassett, John J.;Robitaille, Melanie;Monteith, Gregory R.
通讯作者：
Monteith, Gregory R.