Mediator complex subunit 12 is a gatekeeper of SARS-CoV-2 infection in breast cancer cells.
Mediator complex subunit 12 is a gatekeeper of SARS-CoV-2 infection in breast cancer cells.
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DOI：
10.1016/j.gendis.2021.08.001
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发表时间：
2022-01
期刊：
影响因子：
6.8
通讯作者：
Xu W
中科院分区：
文献类型：
--
作者：
Zhang S;Liu F;Halfmann P;Behrens RT;Liu P;Mcilwain SJ;Ong IM;Donahue K;Wang Y;Kawaoka Y;Sherer N;Xu W
癌症患者感染严重急性呼吸综合征冠状病毒2 （SARS-CoV-2）和死亡的风险增加。与SARS家族中的其他病毒一样，SARS- cov -2利用两种宿主蛋白——血管紧张素转换酶2 （ACE2）和跨膜丝氨酸蛋白酶2 （TMPRSS2）——来进入病毒。最近的研究表明，许多被确定为开发COVID疗法的潜在靶点的宿主蛋白在癌症中表达异常，2促使我们研究人类癌细胞是否容易感染SARS-CoV-2，以及化疗是否可以调节癌症患者的感染风险。乳腺癌是世界上最常见的癌症之一。ACE2和TMRPSS2在细胞系和组织中的表达水平如图1a - c所示。CAL-51是一种表达可检测水平的ACE2和TMPRSS2蛋白的乳腺癌细胞系（图S1D），被发现对SARS-CoV-2具有容忍度。据我们所知，CAL-51是第一个易受SARS-CoV-2感染的乳腺癌细胞系。为了确定化疗是否影响SARS-CoV-2的传染性，我们测量了用氟尿嘧啶（5-FU）、阿霉素、紫杉醇和多西紫杉醇治疗CAL-51细胞后的ACE2蛋白水平（图S2A-D）。Western blotting显示，5-FU和阿霉素显著提高了ACE2水平，而紫杉醇和多西紫杉醇对CAL-51无影响（图1a， S2E）。有趣的是，用临床相关浓度的5-FU和阿霉素预处理细胞，根据这些药物诱导的ACE2水平升高，分别显著和适度地增加了SARS-CoV-2的传染性（图1b， S2F）。相反，紫杉醇和多西紫杉醇治疗在低剂量时轻微抑制了SARS-CoV-2在CAL-51细胞中的感染性，而在高剂量时则没有效果（图S2G， H）。化疗对ACE2表达和SARS-CoV-2尖峰介导的进入的不同影响意味着紫杉醇和多西紫杉醇可能是比5-FU和阿霉素更安全的乳腺癌治疗选择。
Cancer patients are at increased risk for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and mortality. Like other viruses in the SARS family, SARS-CoV-2 employs two host proteins, angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2), for viral entry. 1 Recent studies showed that many of the host proteins identified as potential targets for developing COVID therapies are dysregulated in cancer, 2 prompting us to investigate whether human cancer cells are susceptible to SARS-CoV-2 infection, and whether chemotherapy could modulate a cancer patient's risk for infection.Breast cancer is one of the most frequent cancer diagnoses worldwide. The expression levels of ACE2 and TMRPSS2 among cell lines and tissues are shown in Figure S1A–C. CAL-51, a breast cancer cell line expressing detectable level of ACE2 and TMPRSS2 proteins (Fig. S1D), was found permissive to SARS-CoV-2. To our knowledge, CAL-51 is the first breast cancer cell line susceptible to SARS-CoV-2 infection. To determine whether chemotherapy affects SARS-CoV-2 infectivity, we measured ACE2 protein levels after treating CAL-51 cells with fluorouracil (5-FU), doxorubicin, paclitaxel, and docetaxel (Fig. S2A–D). Western blotting showed that 5-FU and doxorubicin significantly increased ACE2 levels, whereas paclitaxel and docetaxel had no effect in CAL-51 (Fig. 1 A, S2E). Interestingly, pre-treatment of cells with clinically relevant concentrations of 5-FU and doxorubicin significantly and modestly increased SARS-CoV-2 infectivity, respectively (Fig. 1 B, S2F) in accordance with the increased ACE2 levels induced by these drugs. On the contrary, paclitaxel and docetaxel treatment slightly inhibited the infectivity of SARS-CoV-2 in CAL-51 cells at lower doses and had no effect at higher doses (Fig. S2G, H). The differential effects of chemotherapies on ACE2 expression and SARS-CoV-2 Spike-mediated entry imply that paclitaxel and docetaxel may be safer options than 5-FU and doxorubicin for breast cancer treatment.
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DOI：
10.1126/science.abe9403
发表时间：
2020-12-04
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Gordon DE;Hiatt J;Bouhaddou M;Rezelj VV;Ulferts S;Braberg H;Jureka AS;Obernier K;Guo JZ;Batra J;Kaake RM;Weckstein AR;Owens TW;Gupta M;Pourmal S;Titus EW;Cakir M;Soucheray M;McGregor M;Cakir Z;Jang G;O'Meara MJ;Tummino TA;Zhang Z;Foussard H;Rojc A;Zhou Y;Kuchenov D;Hüttenhain R;Xu J;Eckhardt M;Swaney DL;Fabius JM;Ummadi M;Tutuncuoglu B;Rathore U;Modak M;Haas P;Haas KM;Naing ZZC;Pulido EH;Shi Y;Barrio-Hernandez I;Memon D;Petsalaki E;Dunham A;Marrero MC;Burke D;Koh C;Vallet T;Silvas JA;Azumaya CM;Billesbølle C;Brilot AF;Campbell MG;Diallo A;Dickinson MS;Diwanji D;Herrera N;Hoppe N;Kratochvil HT;Liu Y;Merz GE;Moritz M;Nguyen HC;Nowotny C;Puchades C;Rizo AN;Schulze-Gahmen U;Smith AM;Sun M;Young ID;Zhao J;Asarnow D;Biel J;Bowen A;Braxton JR;Chen J;Chio CM;Chio US;Deshpande I;Doan L;Faust B;Flores S;Jin M;Kim K;Lam VL;Li F;Li J;Li YL;Li Y;Liu X;Lo M;Lopez KE;Melo AA;Moss FR 3rd;Nguyen P;Paulino J;Pawar KI;Peters JK;Pospiech TH Jr;Safari M;Sangwan S;Schaefer K;Thomas PV;Thwin AC;Trenker R;Tse E;Tsui TKM;Wang F;Whitis N;Yu Z;Zhang K;Zhang Y;Zhou F;Saltzberg D;QCRG Structural Biology Consortium;Hodder AJ;Shun-Shion AS;Williams DM;White KM;Rosales R;Kehrer T;Miorin L;Moreno E;Patel AH;Rihn S;Khalid MM;Vallejo-Gracia A;Fozouni P;Simoneau CR;Roth TL;Wu D;Karim MA;Ghoussaini M;Dunham I;Berardi F;Weigang S;Chazal M;Park J;Logue J;McGrath M;Weston S;Haupt R;Hastie CJ;Elliott M;Brown F;Burness KA;Reid E;Dorward M;Johnson C;Wilkinson SG;Geyer A;Giesel DM;Baillie C;Raggett S;Leech H;Toth R;Goodman N;Keough KC;Lind AL;Zoonomia Consortium;Klesh RJ;Hemphill KR;Carlson-Stevermer J;Oki J;Holden K;Maures T;Pollard KS;Sali A;Agard DA;Cheng Y;Fraser JS;Frost A;Jura N;Kortemme T;Manglik A;Southworth DR;Stroud RM;Alessi DR;Davies P;Frieman MB;Ideker T;Abate C;Jouvenet N;Kochs G;Shoichet B;Ott M;Palmarini M;Shokat KM;García-Sastre A;Rassen JA;Grosse R;Rosenberg OS;Verba KA;Basler CF;Vignuzzi M;Peden AA;Beltrao P;Krogan NJ
通讯作者：
Krogan NJ
DOI：
10.1101/2020.03.22.002386
发表时间：
2020-03-27
期刊：
bioRxiv : the preprint server for biology
影响因子：
--
作者：
Gordon, David E;Jang, Gwendolyn M;Krogan, Nevan J
通讯作者：
Krogan, Nevan J
影响因子：
64.5
作者：
Hoffmann, Markus;Kleine-Weber, Hannah;Poehlmann, Stefan
通讯作者：
Poehlmann, Stefan
影响因子：
64.5
作者：
Blanco-Melo, Daniel;Nilsson-Payant, Benjamin E.;tenOever, Benjamin R.
通讯作者：
tenOever, Benjamin R.
影响因子：
64.5
作者：
Schneider WM;Luna JM;Hoffmann HH;Sánchez-Rivera FJ;Leal AA;Ashbrook AW;Le Pen J;Ricardo-Lax I;Michailidis E;Peace A;Stenzel AF;Lowe SW;MacDonald MR;Rice CM;Poirier JT
通讯作者：
Poirier JT