紫杉醇是紅豆杉屬植物中的一種復(fù)雜的次生代謝產(chǎn)物, 也是目前所了解的惟一一種可以促進(jìn)微管聚合和穩(wěn)定已聚合微管的藥物。臨床研究表明,，紫杉醇是乳腺癌的有效抑制藥物,。盡管如此，癌細(xì)胞抗紫杉醇作用目前仍然是一個主要的臨床挑戰(zhàn),。當(dāng)前,，急需更好的理解紫杉醇抗性表型來發(fā)現(xiàn)能夠預(yù)測腫瘤對紫杉醇應(yīng)答的生物標(biāo)記物。近日,，美國喬治敦大學(xué)的Ayesha N. Shajahan等人發(fā)現(xiàn),，在雌性激素受體α (ER+)乳腺癌細(xì)胞中，當(dāng)應(yīng)答于低劑量(10nM)的紫杉醇時(shí),，小窩蛋白1(CAV1)的Y14結(jié)構(gòu)域被磷酸化,，導(dǎo)致BCL2的磷酸化水平提升，結(jié)果線粒體發(fā)生凋亡,。相關(guān)研究發(fā)表在3月20日美國《生化周刊》（Journal of Biological Chemistry）上,。
CAV1存在兩種突變體，包括全長形式的CAV1α (野生型CAV1或者是wtCAV1)以及縮短形式的CAV1β,，只有wtCAV1在N端有Y14結(jié)構(gòu)域,。CAV1突變體在細(xì)胞內(nèi)的精確功能還未可知。Ayesha N. Shajahan發(fā)現(xiàn),，CAV1突變體在由紫杉醇介導(dǎo)的細(xì)胞凋亡以及細(xì)胞存活中起著完全不同的作用,。與對紫杉醇敏感的細(xì)胞相比較，在紫杉醇抗性的細(xì)胞中CAV1β水平被顯著提升,。
在對紫杉醇敏感的細(xì)胞中,，CAV1β的表達(dá)顯著的降低了它們對紫杉醇的應(yīng)答能力。這些過程反應(yīng)了Y14的磷酸化具有重要作用,。wtCAV1表達(dá)后,，會磷酸化Y14結(jié)構(gòu)域，結(jié)果激活氨基末端激酶 (JNK),，鈍化BCL2 and BCLxL,。表達(dá)Y14F（缺陷的Y14結(jié)構(gòu)）的MCF-7細(xì)胞會抗紫杉醇，但是可以通過ABT-737（一種BH3類似的小分子抑制物）的聯(lián)合治療而重新獲得對紫杉醇的敏感性,。
使用結(jié)構(gòu)同源建模,，研究人員發(fā)現(xiàn)Y14結(jié)構(gòu)的磷酸化使得蛋白以一種有利構(gòu)象去結(jié)合CAV1支架結(jié)構(gòu)域(CSD)。因此,，研究人員著重突出了CAV1突變體在細(xì)胞死亡中的新奇作用：即wtCAV1會促進(jìn)細(xì)胞死亡,；然而在紫杉醇介導(dǎo)的細(xì)胞凋亡中,，通過JNK鈍化BCL2及BCLxL，CAV1β促進(jìn)了細(xì)胞存活,。（生物谷Deepblue編譯）
doi: 10.1074/jbc.M111.304022
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Tyrosine phosphorylated caveolin-1 (Y14) increases sensitivity to paclitaxel by inhibiting BCL2 and BCLxL via JNK
Ayesha N. Shajahan, Zachary C. Dobbin, F. Edward Hickman, Sivanesan Dakshanamurthy and Robert Clarke.
Paclitaxel, an anti-microtubule agent, is an effective chemotherapeutic drug in breast cancer. Nonetheless, resistance to paclitaxel remains a major clinical challenge. The need to better understand the resistant phenotype, and to find biomarkers that could predict tumor response to paclitaxel is urgent. In estrogen receptor α (ER+) breast cancer cells, phosphorylation of caveolin-1 (CAV1) on Y14 facilitates mitochondrial apoptosis by increasing BCL2 phosphorylation in response to low dose paclitaxel (10 nM).Two variants of CAV1 exist; the full-length form CAV1α (wild-type CAV1 or wtCAV1) and a truncated form CAV1β. The precise cellular functions of CAV1 variants are unknown. Only wtCAV1 has the Y14 region at the N-terminus and we now show that CAV1 variants play distinct roles in paclitaxel-mediated cell death/survival. CAV1β is increased in paclitaxel-resistant cells compared to that in sensitive cells.Expression of CAV1β in sensitive cells significantly reduces their responsiveness to paclitaxel. These activities reflect the essential role for Y14 phosphorylation since wtCAV1 expression, but not a phosphorylation-deficient mutant (Y14F), inactivates BCL2 and BCLxL through activation of c-jun N-terminal kinase (JNK). MCF-7 cells that express Y14F are resistant to paclitaxel and are re-sensitized by co-treatment with ABT-737, a BH3-mimetic small molecule inhibitor.Using structural homology modeling, we propose that phosphorylation on Y14 enables a favorable conformation for proteins to bind to the CAV1 scaffolding domain (CSD). Thus, we highlight novel roles for CAV1 variants in cell death: wtCAV1 promotes cell death whereas CAV1β promotes cell survival by preventing inactivation of BCL2 and BCLxL via JNK in paclitaxel-mediated apoptosis
