A role for macroautophagy in protection against 4-hydroxytamoxifen-induced cell death and the development of antiestrogen resistance
A role for macroautophagy in protection against 4-hydroxytamoxifen-induced cell death and the development of antiestrogen resistance
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DOI：
10.1158/1535-7163.mct-08-0447
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发表时间：
2008-09-01
影响因子：
5.7
通讯作者：
Schoenlein, Patricia V.
中科院分区：
文献类型：
--
作者：
Samaddar, Julia S.;Gaddy, Virgil T.;Schoenlein, Patricia V.
这项研究确定了大自噬作为雌激素受体阳性（ER+）乳腺癌细胞接受4-羟基他莫昔芬（4-OHT）治疗的细胞存活的关键机制。这种选择性ER调节剂是他莫昔芬的活性代谢物，通常用于治疗乳腺癌。我们的研究提供了以下关键发现：（a）在体外用4-OHT处理的乳腺癌细胞中只有20%至25%通过半胱天冬酶依赖性细胞死亡而死亡;更典型地，抗雌激素处理的ER+乳腺癌细胞表达增加的大自噬水平并且是存活的;（B）4-OHT诱导的细胞死亡，而不是4-OHT诱导的大自噬，可以被泛半胱天冬酶抑制剂z-VAD-favorite阻断，提供强有力的证据，证明抗雌激素治疗的这两种结果并不必然相关;（c）选自ER+乳腺癌细胞的4-OHT-抗性细胞显示出增加的经历抗雌激素-受体结合的能力。诱导的大自噬而不诱导半胱天冬酶依赖性细胞死亡;和（d）4-OHT，当与自噬体功能抑制剂组合使用时，诱导ER+、4-OHT抗性乳腺癌细胞的稳健的半胱天冬酶依赖性凋亡。据我们所知，这些研究提供了第一个证据表明，巨自噬在抗雌激素抵抗的发展中起着至关重要的作用。我们提出，靶向自噬体功能将提高ER+乳腺癌的激素治疗的疗效。
This study identifies macroautophagy as a key mechanism of cell survival in estrogen receptor-positive (ER+) breast cancer cells undergoing treatment with 4-hydroxytamoxifen (4-OHT). This selective ER modifier is an active metabolite of tamoxifen commonly used for the treatment of breast cancer. Our study provides the following key findings: (a) only 20% to 25% of breast cancer cells treated with 4-OHT in vitro die via caspase-dependent cell death; more typically, the anti estrogen-treated ER+ breast cancer cells express increased levels of macroautophagy and are viable; (b) 4-OHT-induced cell death, but not 4-OHT-induced macroautophagy, can be blocked by the pan-caspase inhibitor z-VAD-fmk, providing strong evidence that these two outcomes of antiestrogen treatment are not linked in an obligatory manner; (c) 4-OHT-resistant cells selected from ER+ breast cancer cells show an increased ability to undergo antiestrogen-induced macroautophagy without induction of caspase-dependent cell death; and (d) 4-OHT, when used in combination with inhibitors of autophagosome function, induces robust, caspase-dependent apoptosis of ER+, 4-OHT-resistant breast cancer cells. To our knowledge, these studies provide the first evidence that macroautophagy plays a critical role in the development of antiestrogen resistance. We propose that targeting autophagosome function will improve the efficacy of hormonal treatment of ER+ breast cancer.