Glucocorticoids induce differentiation and chemoresistance in ovarian cancer by promoting ROR1-mediated stemness.
Glucocorticoids induce differentiation and chemoresistance in ovarian cancer by promoting ROR1-mediated stemness.
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DOI：
10.1038/s41419-020-03009-4
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发表时间：
2020-09-23
影响因子：
9
通讯作者：
Ungureanu D
中科院分区：
文献类型：
--
作者：
Karvonen H;Arjama M;Kaleva L;Niininen W;Barker H;Koivisto-Korander R;Tapper J;Pakarinen P;Lassus H;Loukovaara M;Bützow R;Kallioniemi O;Murumägi A;Ungureanu D
糖皮质激素在临床上通常用作抗炎剂和免疫抑制剂以及癌症治疗期间的佐剂，以减轻化疗的不良副作用。然而，最近的研究表明，糖皮质激素可能会通过促进肿瘤细胞存活、异质性和转移而对化疗的疗效产生负面影响。在这里，我们发现地塞米松诱导卵巢癌（OC）中ROR 1表达上调，包括铂耐药OC。ROR 1表达的增加导致一组OC细胞系以及原发性卵巢癌患者来源的细胞中RhoA、雅普/TAZ和BMI-1水平升高，强调了我们研究的翻译相关性。重要的是，地塞米松诱导分化的OC患者来源的细胞离体根据其分子亚型和细胞分化标志物的表型表达。对OC细胞系和患者来源细胞的528种新兴和临床肿瘤学化合物进行的高通量药物测试显示，地塞米松治疗增加了对几种AKT/PI 3 K靶向激酶抑制剂的敏感性，同时显著降低了紫杉烷等化疗药物以及SMAC模拟物等抗凋亡化合物的疗效。另一方面，靶向ROR 1表达增加了紫杉烷类药物和SMAC模拟物的疗效，提示了OC患者的新组合靶向治疗。
Glucocorticoids are routinely used in the clinic as anti-inflammatory and immunosuppressive agents as well as adjuvants during cancer treatment to mitigate the undesirable side effects of chemotherapy. However, recent studies have indicated that glucocorticoids may negatively impact the efficacy of chemotherapy by promoting tumor cell survival, heterogeneity, and metastasis. Here, we show that dexamethasone induces upregulation of ROR1 expression in ovarian cancer (OC), including platinum-resistant OC. Increased ROR1 expression resulted in elevated RhoA, YAP/TAZ, and BMI-1 levels in a panel of OC cell lines as well as primary ovarian cancer patient-derived cells, underlining the translational relevance of our studies. Importantly, dexamethasone induced differentiation of OC patient-derived cells ex vivo according to their molecular subtype and the phenotypic expression of cell differentiation markers. High-throughput drug testing with 528 emerging and clinical oncology compounds of OC cell lines and patient-derived cells revealed that dexamethasone treatment increased the sensitivity to several AKT/PI3K targeted kinase inhibitors, while significantly decreasing the efficacy of chemotherapeutics such as taxanes, as well as anti-apoptotic compounds such as SMAC mimetics. On the other hand, targeting ROR1 expression increased the efficacy of taxane drugs and SMAC mimetics, suggesting new combinatorial targeted treatments for patients with OC.
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影响因子：
7.3
作者：
Cai Q;Sun H;Peng Y;Lu J;Nikolovska-Coleska Z;McEachern D;Liu L;Qiu S;Yang CY;Miller R;Yi H;Zhang T;Sun D;Kang S;Guo M;Leopold L;Yang D;Wang S
通讯作者：
Wang S
影响因子：
6.2
作者：
Noonan AM;Bunch KP;Chen JQ;Herrmann MA;Lee JM;Kohn EC;O'Sullivan CC;Jordan E;Houston N;Takebe N;Kinders RJ;Cao L;Peer CJ;Figg WD;Annunziata CM
通讯作者：
Annunziata CM
影响因子：
30.8
作者：
Lee, Jin-Ku;Liu, Zhaoqi;Nam, Do-Hyun
通讯作者：
Nam, Do-Hyun
DOI：
10.1038/nrc4019
发表时间：
2015-11
期刊：
Nature reviews. Cancer
影响因子：
--
作者：
Bowtell DD;Böhm S;Ahmed AA;Aspuria PJ;Bast RC Jr;Beral V;Berek JS;Birrer MJ;Blagden S;Bookman MA;Brenton JD;Chiappinelli KB;Martins FC;Coukos G;Drapkin R;Edmondson R;Fotopoulou C;Gabra H;Galon J;Gourley C;Heong V;Huntsman DG;Iwanicki M;Karlan BY;Kaye A;Lengyel E;Levine DA;Lu KH;McNeish IA;Menon U;Narod SA;Nelson BH;Nephew KP;Pharoah P;Powell DJ Jr;Ramos P;Romero IL;Scott CL;Sood AK;Stronach EA;Balkwill FR
通讯作者：
Balkwill FR
影响因子：
13.8
作者：
Kadmiel M;Cidlowski JA
通讯作者：
Cidlowski JA