Increase of doxorubicin-induced apoptosis after knock-down of gonadotropin-releasing hormone receptor expression in human endometrial, ovarian and breast cancer cells
Increase of doxorubicin-induced apoptosis after knock-down of gonadotropin-releasing hormone receptor expression in human endometrial, ovarian and breast cancer cells
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DOI：
10.1080/09513590701668882
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发表时间：
2008-01-01
影响因子：
2
通讯作者：
Gruendker, Carsten
中科院分区：
文献类型：
--
作者：
Fister, Stefanie;Schlotawa, Lars;Gruendker, Carsten
大多数人子宫内膜癌、卵巢癌和乳腺癌表达促性腺激素释放激素（GnRH）受体。GnRH及其激动剂类似物可使其增殖呈时间和剂量依赖性降低。GnRH激动剂;通过激活磷酸酪氨酸磷酸酶抑制生长因子受体的促有丝分裂信号转导，导致癌细胞增殖下调。不涉及细胞凋亡的诱导。最近，我们发现，促性腺激素释放激素激动剂曲普瑞林诱导核因子-κ B（NF κ B）的激活，从而减少细胞毒性剂阿霉素诱导的人子宫内膜癌和卵巢癌细胞的凋亡。通过抑制NF κ B B易位入核阻断曲普瑞林诱导的多柔比星诱导的细胞凋亡减少。本研究旨在探讨GnRH受体表达的敲低是否减少GnRH激动剂诱导的抗凋亡作用。我们发现，在人子宫内膜癌和卵巢癌以及人乳腺癌细胞系MCF-7中，GnRH受体表达的敲低导致阿霉素诱导的细胞凋亡增加。这些数据进一步表明，GnRH激动剂通过激活这些癌症中的GnRH受体抑制化疗药物诱导的细胞凋亡。这种情况与T-47-D乳腺癌细胞不同。GnRH受体表达敲低后，阿霉素诱导的细胞凋亡减少，表明GnRH激动剂不能抑制化疗药物诱导的T-47-D乳腺癌细胞凋亡。
The majority of human endometrial, ovarian and breast cancers express receptors for gonadotropin-releasing hormone (GnRH). Their proliferation is time- and dose-dependently reduced by GnRH and its agonistic analogs. GnRH agonists; inhibit the mitogenic signal transduction of growth factor receptors via activation of a phosphotyrosine phosphatase, resulting in downregulation of cancer cell proliferation. Induction of apoptosis is not involved. Recently we showed that the GnRH agonist triptorelin induces activation of nuclear factor-kappa B (NF kappa B) and thus reduces the apoptosis induced by the cytotoxic agent doxorubicin in human endometrial and ovarian cancer cells. The triptorelin-induced reduction of doxorubicin-induced apoptosis was blocked by inhibition of NF kappa B translocation into the nucleus.The present study was conducted to investigate whether knock-down of GnRH receptor expression reduces GnRH agonist-induced anti-apoptotic action. We show that knock-down of GnRH receptor expression results in an increase of doxorubicin-induced apoptosis in human endometrial and ovarian cancers and in the human breast cancer cell line MCF-7. These data further demonstrate that GnRH agonists suppress chemotherapeutic drug-induced apoptosis via activation of the GnRH receptor in these cancers. The situation is different with T-47-D breast cancer cells. After knock-down of GnRH receptor expression doxorubicin-induced apoptosis was decreased, indicating that GnRH agonists; do not suppress chemotherapeutic drug-induced apoptosis in T-47-D breast cancer cells.