Protein and chemotherapy profiling of extracellular vesicles harvested from therapeutic induced senescent triple negative breast cancer cells.
Protein and chemotherapy profiling of extracellular vesicles harvested from therapeutic induced senescent triple negative breast cancer cells.
复制标题
DOI：
10.1038/oncsis.2017.82
复制
发表时间：
2017-10-09
期刊：
影响因子：
6.2
通讯作者：
McCann A
中科院分区：
文献类型：
--
作者：
Kavanagh EL;Lindsay S;Halasz M;Gubbins LC;Weiner-Gorzel K;Guang MHZ;McGoldrick A;Collins E;Henry M;Blanco-Fernández A;O Gorman P;Fitzpatrick P;Higgins MJ;Dowling P;McCann A
三阴性乳腺癌(TNBC)是一种侵袭性亚型，临床预后相对较差，治疗选择有限。化疗在杀死癌细胞的同时，可能导致产生高度耐药的治疗性诱导衰老(TIS)细胞，这些细胞可能形成干细胞利基，从而导致转移。有趣的是，衰老细胞比非衰老细胞释放更多的胞外小泡(EVS)。我们的目的是将从TIS TNBC细胞中获得的EVS与对照细胞进行比较，以确定TIS TNBC细胞在化疗中维持存活的潜在机制。用化疗药物紫杉醇(Taxol)诱导和证实了Cal51TNBC细胞的TIS。用Invenity Path Analysis和InnateDB程序对从TIS获得的EV与对照Cal51细胞进行了质谱仪(MS)分析。我们发现，经75 NM PTX处理7天的TIS Cal51细胞发生衰老(衰老相关β-半乳糖苷酶(SA-β-Gal)阳性，Ki67阴性，p21和p16增加，G2/M期停滞)，释放更多的EV(P=0.0002)和外切体(P=0.0007)。此外，TIS细胞多药耐药蛋白1/p-糖蛋白表达增加。MS分析表明，衰老的Cal51细胞来源的EVS含有142个蛋白质，与对照EVS相比，EVS的倍增显著增加。关键蛋白包括ATPase、膜联蛋白、微管蛋白、整合素、RABS和不溶性衰老相关分泌表型(SASP)因子。一种PTX的荧光类似物(FluTax-2)允许评价从衰老细胞中去除EVS中的化疗。外切体生物合成抑制剂GW4869处理TIS细胞后，SA-β-Gal染色减弱(P=0.04)。综上所述，本研究表明TIS细胞比对照细胞释放更多的EVS，包括化疗和参与细胞增殖、ATP耗竭、细胞凋亡和SASP的关键蛋白。这些发现可能部分解释了为什么癌症衰老细胞在化疗挑战下仍能存活。
Triple negative breast cancer (TNBC) is an aggressive subtype with relatively poor clinical outcomes and limited treatment options. Chemotherapy, while killing cancer cells, can result in the generation of highly chemoresistant therapeutic induced senescent (TIS) cells that potentially form stem cell niches resulting in metastases. Intriguingly, senescent cells release significantly more extracellular vesicles (EVs) than non-senescent cells. Our aim was to profile EVs harvested from TIS TNBC cells compared with control cells to identify a potential mechanism by which TIS TNBC cells maintain survival in the face of chemotherapy. TIS was induced and confirmed in Cal51 TNBC cells using the chemotherapeutic paclitaxel (PTX) (Taxol). Mass spectrometry (MS) analysis of EVs harvested from TIS compared with control Cal51 cells was performed using Ingenuity Pathway Analysis and InnateDB programs. We demonstrate that TIS Cal51 cells treated with 75 nM PTX for 7 days became senescent (senescence-associated β-galactosidase (SA-β-Gal) positive, Ki67-negative, increased p21 and p16, G2/M cell cycle arrest) and released significantly more EVs (P=0.0002) and exosomes (P=0.0007) than non-senescent control cells. Moreover, TIS cells displayed an increased expression of the multidrug resistance protein 1/p-glycoprotein. MS analysis demonstrated that EVs derived from senescent Cal51 cells contained 142 proteins with a significant increased fold change compared with control EVs. Key proteins included ATPases, annexins, tubulins, integrins, Rabs and insoluble senescence-associated secretory phenotype (SASP) factors. A fluorescent analogue of PTX (Flutax-2) allowed appreciation of the removal of chemotherapy in EVs from senescent cells. Treatment of TIS cells with the exosome biogenesis inhibitor GW4869 resulted in reduced SA-β-Gal staining (P=0.04). In summary, this study demonstrates that TIS cells release significantly more EVs compared with control cells, containing chemotherapy and key proteins involved in cell proliferation, ATP depletion, apoptosis and the SASP. These findings may partially explain why cancer senescent cells remain viable despite chemotherapeutic challenge.
登录
查看更多内容
来自耐药乳腺癌细胞的外泌体通过 MicroRNA 的水平转移传递化疗耐药性
影响因子：
3.7
作者：
Chen WX;Liu XM;Lv MM;Chen L;Zhao JH;Zhong SL;Ji MH;Hu Q;Luo Z;Wu JZ;Tang JH
通讯作者：
Tang JH
DOI：
10.1146/annurev-pathol-121808-102144
发表时间：
2010
期刊：
Annual review of pathology
影响因子：
--
作者：
Coppé JP;Desprez PY;Krtolica A;Campisi J
通讯作者：
Campisi J
影响因子：
21.3
作者：
Costa-Silva B;Aiello NM;Ocean AJ;Singh S;Zhang H;Thakur BK;Becker A;Hoshino A;Mark MT;Molina H;Xiang J;Zhang T;Theilen TM;García-Santos G;Williams C;Ararso Y;Huang Y;Rodrigues G;Shen TL;Labori KJ;Lothe IM;Kure EH;Hernandez J;Doussot A;Ebbesen SH;Grandgenett PM;Hollingsworth MA;Jain M;Mallya K;Batra SK;Jarnagin WR;Schwartz RE;Matei I;Peinado H;Stanger BZ;Bromberg J;Lyden D
通讯作者：
Lyden D
影响因子：
15.9
作者：
Leca, Julie;Martinez, Sebastien;Tomasini, Richard
通讯作者：
Tomasini, Richard
影响因子：
9.7
作者：
Alasmael, Noura;Mohan, Rati;Plant, Nick J.
通讯作者：
Plant, Nick J.