Anticipatory estrogen activation of the unfolded protein response is linked to cell proliferation and poor survival in estrogen receptor α-positive breast cancer.
Anticipatory estrogen activation of the unfolded protein response is linked to cell proliferation and poor survival in estrogen receptor α-positive breast cancer.
复制标题
作者：
在细胞应激反应中，癌细胞经常激活内质网（EnR）应激传感器，即未折叠蛋白反应（UPR）。对于不同的UPR激活模式在癌症中的潜在作用知之甚少；在未折叠蛋白积累或细胞应激之前UPR的预期激活。我们发现，雌激素通过雌激素受体α (ERα)作用，诱导UPR的快速预期激活，导致抗凋亡伴侣BiP/GRP78的产生增加，为随后雌激素受体α诱导的细胞增殖所需的蛋白质产量增加做准备。在含有ERα的癌细胞中，雌激素17β-雌二醇（E2）通过磷脂酶Cγ (PLCγ)介导的EnR IP3R钙通道开放激活UPR，使钙从EnR管腔进入细胞质。siRNA敲低ERα阻断了雌激素介导的细胞质钙和UPR激活的增加。PLCγ或IP3R的敲低或抑制强烈抑制雌激素介导的细胞质钙、UPR激活和细胞增殖的增加。E2-ERα激活培养的乳腺癌和卵巢癌细胞和小鼠异种移植物中UPR的所有三个臂。下调调节UPR伴侣蛋白的ATF6α可阻断雌激素对BiP的诱导，强烈抑制E2-ERα刺激的细胞增殖。雌激素轻度和短暂的UPR激活促进适应性UPR反应，保护细胞免受随后UPR介导的凋亡。来自ERα阳性乳腺癌的数据分析表明，UPR基因标志的表达升高，这是一种强大的新预后标志物，与随后对他莫昔芬治疗的耐药、复发时间缩短和生存率低密切相关。因此，作为E2-ERα增殖程序的早期组成部分，有丝分裂原雌激素驱动UPR的快速预期激活。UPR的预期激活是雌激素在癌细胞增殖和治疗抵抗中的新作用。
In response to cell stress, cancer cells often activate the endoplasmic reticulum (EnR) stress sensor, the unfolded protein response (UPR). Little was known about the potential role in cancer of a different mode of UPR activation; anticipatory activation of the UPR prior to accumulation of unfolded protein or cell stress. We show that estrogen, acting via estrogen receptor α (ERα), induces rapid anticipatory activation of the UPR, resulting in increased production of the antiapoptotic chaperone BiP/GRP78, preparing cancer cells for the increased protein production required for subsequent estrogen-ERα induced cell proliferation. In ERα containing cancer cells, the estrogen, 17β-estradiol (E2) activates the UPR through a phospholipase C γ (PLCγ)-mediated opening of EnR IP3R calcium channels, enabling passage of calcium from the lumen of the EnR into the cytosol. siRNA knockdown of ERα blocked the estrogen-mediated increase in cytosol calcium and UPR activation. Knockdown or inhibition of PLCγ, or of IP3R, strongly inhibited the estrogen-mediated increases in cytosol calcium, UPR activation and cell proliferation. E2-ERα activates all three arms of the UPR in breast and ovarian cancer cells in culture and in a mouse xenograft. Knockdown of ATF6α, which regulates UPR chaperones, blocked estrogen induction of BiP and strongly inhibited E2-ERα stimulated cell proliferation. Mild and transient UPR activation by estrogen promotes an adaptive UPR response that protects cells against subsequent UPR-mediated apoptosis. Analysis of data from ERα positive breast cancers demonstrates elevated expression of a UPR gene signature that is a powerful new prognostic marker tightly correlated with subsequent resistance to tamoxifen therapy, reduced time to recurrence and poor survival. Thus, as an early component of the E2-ERα proliferation program, the mitogen estrogen, drives rapid anticipatory activation of the UPR. Anticipatory activation of the UPR is a new role for estrogens in cancer cell proliferation and resistance to therapy.
登录
查看更多内容
影响因子：
--
作者：
Andruska, Neal;Mao, Chengjian;Shapiro, David J.
通讯作者：
Shapiro, David J.
影响因子：
8.8
作者：
通讯作者：
--
影响因子：
11.2
作者：
Fu, Yong;Li, Jianze;Lee, Amy S.
通讯作者：
Lee, Amy S.
DOI：
10.1073/pnas.1115188108
发表时间：
2011-11-22
影响因子：
11.1
作者：
Ariazi, Eric A.;Cunliffe, Heather E.;Jordan, V. Craig
通讯作者：
Jordan, V. Craig
影响因子：
3.8
作者：
Rae, JM;Johnson, MD;Lippman, ME
通讯作者：
Lippman, ME