Cell fate regulation by gelsolin in human gynecologic cancers
Cell fate regulation by gelsolin in human gynecologic cancers
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DOI：
10.1073/pnas.1401166111
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发表时间：
2014-10-07
影响因子：
11.1
通讯作者：
Tsang, Benjamin K.
中科院分区：
文献类型：
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作者：
Abedini, Mohammad R.;Wang, Pei-Wen;Tsang, Benjamin K.
化疗耐药性是癌症治疗的主要障碍。细胞凋亡通路的下调是化疗耐药的关键决定因素之一。在这里，我们报道了化疗耐药的妇科癌细胞中gelsolin （GSN）水平高于敏感的同类细胞。顺式二胺二氯铂（CDDP）诱导的GSN下调与其裂解和凋亡有关。虽然c端GSN片段（C-GSN）使化疗耐药细胞对CDDP增敏，但完整的GSN及其n端片段（N-GSN）减弱了这种反应。GSN沉默也促进了cddp诱导的化疗耐药细胞凋亡。相比之下，完整的GSN （I-GSN）在CDDP存在下通过fliclike inhibitory protein (FLIP)-Itch相互作用促进存活。这种相互作用共定位于敏感细胞中可被CDDP解离的核周区域，从而诱导FLIP泛素化和降解，随后发生凋亡。在耐药细胞中，GSN高表达，CDDP未能消除I-GSN-FLIP-Itch相互作用，导致下游反应失调。此外，我们还研究了GSN在卵巢浆液腺癌中的表达与无进展生存期、总生存期以及临床预后的关系。GSN过表达与更具攻击性的行为和更多的癌症死亡显著相关，并支持了我们的假设，即高GSN表达通过改变GSN- flip - itch相互作用赋予癌细胞化疗耐药。这些发现与GSN在调节妇科细胞命运中发挥重要作用的观点一致，这反映在化疗敏感性的失调中。
Chemoresistance is a major hurdle in cancer treatment. Downregulation of apoptosis pathways is one of the key determinants for chemoresistance. Here, we report higher gelsolin (GSN) levels in chemoresistant gynecological cancer cells compared with their sensitive counterparts. cis-Diammine dichloroplatinium (II) (CDDP)induced GSN down-regulation is associated with its cleavage and apoptosis. Although the C-terminal GSN fragment (C-GSN) sensitized chemoresistant cells to CDDP, intact GSN and its N-terminal fragment (N-GSN) attenuated this response. GSN silencing also facilitated CDDP-induced apoptosis in chemoresistant cells. In contrast, intact GSN (I-GSN) was prosurvival in the presence of CDDP through a FLICE-like inhibitory protein (FLIP)-Itch interaction. This interaction was colocalized in the perinuclear region that could be dissociated by CDDP in sensitive cells, thereby inducing FLIP ubiquitination and degradation, followed by apoptosis. In resistant cells, GSN was highly expressed and CDDP failed to abolish the I-GSN-FLIP-Itch interaction, resulting in the dysregulation of the downstream responses. In addition, we investigated the association between GSN expression in ovarian serous adenocarcinoma and progression free survival and overall survival, as well as clinical prognosis. GSN overexpression was significantly associated with more aggressive behavior and more cancer deaths and supported our hypothesis that high GSN expression confers chemoresistance in cancer cells by altering the GSN-FLIP-Itch interaction. These findings are in agreement with the notion that GSN plays an important role in the regulation of gynecological cell fate as reflected in dysregulation in chemosensitivity.