Pseudomonas aeruginosa ExoT induces G1 cell cycle arrest in melanoma cells.
Pseudomonas aeruginosa ExoT induces G1 cell cycle arrest in melanoma cells.
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DOI：
10.1111/cmi.13339
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发表时间：
2021-08
影响因子：
3.4
通讯作者：
Shafikhani SH
中科院分区：
文献类型：
--
作者：
Mohamed MF;Wood SJ;Roy R;Reiser J;Kuzel TM;Shafikhani SH
最近，我们证明了铜绿假单胞菌外毒素T （ExoT）采用两种不同的机制在多种癌细胞系中诱导有效的凋亡细胞毒性。我们进一步证明，它可以显著减少黑色素瘤动物模型的肿瘤生长。在这些研究中，我们观察到转染ExoT的黑色素瘤细胞无法进行有丝分裂，无论它们最终是否屈服于ExoT诱导的凋亡或在ExoT存在下存活。在本报告中，我们试图研究ExoT在黑色素瘤中的抗增殖活性。我们通过细菌（证明必要性）和转染（证明充分性）将ExoT传递到B16黑色素瘤细胞中。我们的数据表明，ExoT在黑色素瘤细胞中具有强大的抗增殖功能。我们发现ExoT通过抑制G1/S检查点蛋白导致黑色素瘤细胞G1间期细胞周期阻滞。我们的数据表明，ExoT的两个域；（adp -核糖基转移酶（ADPRT）结构域和GTPase激活蛋白（GAP）结构域）；有助于exot诱导的黑色素瘤G1细胞周期阻滞。最后，我们发现adprt诱导的黑色素瘤细胞G1细胞周期阻滞可能与Crk衔接蛋白有关。我们的数据揭示了ExoT的一种新的毒力功能，并进一步强调了ExoT治疗癌症的潜力。铜绿假单胞菌ExoT通过抑制G1/S过渡检查点调节因子导致G1细胞周期阻滞，其两个结构域都起作用。GAP结构域可能通过靶向RhoA阻止G1/S检查点的进展，而ADPRT可能通过靶向Crk接头蛋白和干扰锚定依赖性整合素信号传导来阻止G1/S检查点的进展。
Recently, we demonstrated that Pseudomonas aeruginosa Exotoxin T (ExoT) employs two distinct mechanisms to induce potent apoptotic cytotoxicity in a variety of cancer cell lines. We further demonstrated that it can significantly reduce tumor growth in an animal model for melanoma. During these studies, we observed that melanoma cells that were transfected with ExoT failed to undergo mitosis, regardless of whether they eventually succumbed to ExoT-induced apoptosis or survived in ExoT’s presence. In this report, we sought to investigate ExoT’s antiproliferative activity in melanoma. We delivered ExoT into B16 melanoma cells by bacteria (to show necessity) and by transfection (to show sufficiency). Our data indicate that ExoT exerts a potent antiproliferative function in melanoma cells. We show that ExoT causes cell cycle arrest in G1 interphase in melanoma cells by dampening the G1/S checkpoint proteins. Our data demonstrate that both domains of ExoT; (the ADP-ribosyltransferase (ADPRT) domain and the GTPase activating protein (GAP) domain); contribute to ExoT-induced G1 cell cycle arrest in melanoma. Finally, we show that the ADPRT-induced G1 cell cycle arrest in melanoma cells likely involves the Crk adaptor protein. Our data reveal a novel virulence function for ExoT and further highlight the therapeutic potential of ExoT against cancer. Pseudomonas aeruginosa ExoT causes G1 cell cycles arrest by dampening G1/S transition checkpoint regulators, and both of its domains contribute. The GAP domain likely prevents progression through G1/S checkpoint by targeting RhoA and the ADPRT prevents progression through G1/S checkpoint likely by targeting Crk adaptor protein and by interfering with the anchorage-dependent integrin signaling.
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DOI：
10.1111/wrr.12310
发表时间：
2015-07
期刊：
Wound repair and regeneration : official publication of the Wound Healing Society [and] the European Tissue Repair Society
影响因子：
--
作者：
Goldufsky J;Wood SJ;Jayaraman V;Majdobeh O;Chen L;Qin S;Zhang C;DiPietro LA;Shafikhani SH
通讯作者：
Shafikhani SH
影响因子：
11.8
作者：
Gupta KH;Goldufsky JW;Wood SJ;Tardi NJ;Moorthy GS;Gilbert DZ;Zayas JP;Hahm E;Altintas MM;Reiser J;Shafikhani SH
通讯作者：
Shafikhani SH
影响因子：
4.8
作者：
Deng, Q;Sun, JJ;Barbieri, JT
通讯作者：
Barbieri, JT
影响因子：
3.1
作者：
Krall, R;Schmidt, G;Barbieri, JT
通讯作者：
Barbieri, JT
影响因子：
2.7
作者：
Chen, Wen-Juan;Xiong, Zheng-Ai;Wang, Zhi-Gang
通讯作者：
Wang, Zhi-Gang