Targeting Cancer Gene Dependencies with Anthrax-Mediated Delivery of Peptide Nucleic Acids.
Targeting Cancer Gene Dependencies with Anthrax-Mediated Delivery of Peptide Nucleic Acids.
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DOI：
10.1021/acschembio.9b01027
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发表时间：
2020-06-19
影响因子：
4
通讯作者：
Pentelute BL
中科院分区：
文献类型：
--
作者：
Lu Z;Paolella BR;Truex NL;Loftis AR;Liao X;Rabideau AE;Brown MS;Busanovich J;Beroukhim R;Pentelute BL
反义寡核苷酸疗法是重要的癌症治疗方法，其可以抑制癌细胞中对细胞存活至关重要的基因。SF 3B 1是一个很有前途的基因靶点，它编码SF 3B蛋白复合物中的一个关键剪接因子。超过10%的癌症已经失去了SF 3B 1基因的一个或多个拷贝，使这些癌症在进一步抑制后变得脆弱。SF 3B 1只是CYCLOPS（由于部分缺失而产生癌症责任的拷贝数改变）基因的一个例子，但已知有超过120个其他候选CYCLOPS基因。用于癌症的反义寡核苷酸疗法提供了有效抑制CYCLOPS基因的希望，但是由于它们对细胞的有限渗透性和差的胞质稳定性，开发这些治疗是困难的。在这里，我们开发了一种有效的方法来抑制CYCLOPS基因通过提供反义肽核酸（PNA）到癌细胞的胞质溶胶。我们实现了有效的细胞溶质PNA交付与炭疽毒素的两个主要无毒成分：保护性抗原（PA）和263个残基的N-末端结构域的致死因子（LFN）。分选酶介导的连接容易使PNA与LFN蛋白的C末端缀合。LFN和PA协同工作以将PNA易位到哺乳动物细胞的胞质溶胶中。用LFN/PA系统递送的反义SF 3B 1 PNA抑制SF 3B 1基因并降低细胞活力，特别是具有SF 3B 1部分拷贝数损失的癌细胞。此外，与HER 2结合PA变体一起递送的反义SF 3B 1 PNA选择性地靶向过表达HER 2细胞受体的癌细胞，证明了癌细胞的受体特异性靶向。综上所述，我们的努力说明了PA介导的PNA递送如何为递送反义PNA治疗剂和靶向癌症中的基因依赖性提供有效和通用的方法。
Antisense oligonucleotide therapies are important cancer treatments, which can suppress genes in cancer cells that are critical for cell survival. SF3B1 has recently emerged as a promising gene target that encodes a key splicing factor in the SF3B protein complex. Over 10% of cancers have lost one or more copies of the SF3B1 gene, rendering these cancers vulnerable after further suppression. SF3B1 is just one example of a CYCLOPS (Copy-number alterations Yielding Cancer Liabilities Owing to Partial losS) gene, but over 120 additional candidate CYCLOPS genes are known. Antisense oligonucleotide therapies for cancer offer the promise of effective suppression for CYCLOPS genes, but developing these treatments is difficult due to their limited permeability into cells and poor cytosolic stability. Here we develop an effective approach to suppress CYCLOPS genes by delivering antisense peptide nucleic acids (PNAs) into the cytosol of cancer cells. We achieve efficient cytosolic PNA delivery with the two main non-toxic components of the anthrax toxin: protective antigen (PA) and the 263-residue N-terminal domain of lethal factor (LFN). Sortase-mediated ligation readily enables the conjugation of PNAs to the C-terminus of the LFN protein. LFN and PA work together in concert to translocate PNAs into the cytosol of mammalian cells. Antisense SF3B1 PNAs delivered with the LFN/PA system suppress the SF3B1 gene and decrease cell viability, particularly of cancer cells with partial copy-number loss of SF3B1. Moreover, antisense SF3B1 PNAs delivered with a HER2-binding PA variant selectively target cancer cells that over-express the HER2 cell receptor, demonstrating receptor-specific targeting of cancer cells. Taken together, our efforts illustrate how PA-mediated delivery of PNAs provides an effective and general approach for delivering antisense PNA therapeutics and for targeting gene dependencies in cancer.
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影响因子：
64.8
作者：
Ellis, Matthew J.;Ding, Li;Shen, Dong;Luo, Jingqin;Suman, Vera J.;Wallis, John W.;Van Tine, Brian A.;Hoog, Jeremy;Goiffon, Reece J.;Goldstein, Theodore C.;Ng, Sam;Lin, Li;Crowder, Robert;Snider, Jacqueline;Ballman, Karla;Weber, Jason;Chen, Ken;Koboldt, Daniel C.;Kandoth, Cyriac;Schierding, William S.;McMichael, Joshua F.;Miller, Christopher A.;Lu, Charles;Harris, Christopher C.;McLellan, Michael D.;Wendl, Michael C.;DeSchryver, Katherine;Allred, D. Craig;Esserman, Laura;Unzeitig, Gary;Margenthaler, Julie;Babiera, G. V.;Marcom, P. Kelly;Guenther, J. M.;Leitch, Marilyn;Hunt, Kelly;Olson, John;Tao, Yu;Maher, Christopher A.;Fulton, Lucinda L.;Fulton, Robert S.;Harrison, Michelle;Oberkfell, Ben;Du, Feiyu;Demeter, Ryan;Vickery, Tammi L.;Elhammali, Adnan;Piwnica-Worms, Helen;McDonald, Sandra;Watson, Mark;Dooling, David J.;Ota, David;Chang, Li-Wei;Bose, Ron;Ley, Timothy J.;Piwnica-Worms, David;Stuart, Joshua M.;Wilson, Richard K.;Mardis, Elaine R.
通讯作者：
Mardis, Elaine R.
影响因子：
30.8
作者：
Harbour, J. William;Roberson, Elisha D. O.;Anbunathan, Hima;Onken, Michael D.;Worley, Lori A.;Bowcock, Anne M.
通讯作者：
Bowcock, Anne M.
影响因子：
2.9
作者：
Doyle, DF;Braasch, DA;Corey, DR
通讯作者：
Corey, DR
DOI：
10.1073/pnas.93.22.12531
发表时间：
1996-10-29
影响因子：
11.1
作者：
Ballard, JD;Collier, RJ;Starnbach, MN
通讯作者：
Starnbach, MN
影响因子：
64.8
作者：
Hsu TY;Simon LM;Neill NJ;Marcotte R;Sayad A;Bland CS;Echeverria GV;Sun T;Kurley SJ;Tyagi S;Karlin KL;Dominguez-Vidaña R;Hartman JD;Renwick A;Scorsone K;Bernardi RJ;Skinner SO;Jain A;Orellana M;Lagisetti C;Golding I;Jung SY;Neilson JR;Zhang XH;Cooper TA;Webb TR;Neel BG;Shaw CA;Westbrook TF
通讯作者：
Westbrook TF