RUVBL1/RUVBL2 ATPase Activity Drives PAQosome Maturation, DNA Replication and Radioresistance in Lung Cancer.
RUVBL1/RUVBL2 ATPase Activity Drives PAQosome Maturation, DNA Replication and Radioresistance in Lung Cancer.
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DOI：
10.1016/j.chembiol.2019.12.005
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发表时间：
2020-01-16
影响因子：
8.6
通讯作者：
Kittler R
中科院分区：
文献类型：
--
作者：
Yenerall P;Das AK;Wang S;Kollipara RK;Li LS;Villalobos P;Flaming J;Lin YF;Huffman K;Timmons BC;Gilbreath C;Sonavane R;Kinch LN;Rodriguez-Canales J;Moran C;Behrens C;Hirasawa M;Takata T;Murakami R;Iwanaga K;Chen BPC;Grishin NV;Raj GV;Wistuba II;Minna JD;Kittler R
RUVBL 1和RUVBL 2（统称为RUVBL 1/2）是必需的AAA+ ATP酶，其作为辅助分子伴侣发挥作用，并与癌症有关。在这里，我们研究了RUVBL 1/2 ATP酶活性在非小细胞肺癌（NSCLC）中的分子和表型作用。我们发现RUVBL 1/2在NSCLC患者肿瘤中过表达，高表达与低生存率相关。利用RUVBL 1/2 ATP酶活性的特异性抑制剂，我们表明RUVBL 1/2 ATP酶活性是PAQosome成熟或解离所必需的，PAQosome是一种大型RUVBL 1/2依赖性多蛋白复合物。我们还表明RUVBL 1/2在DNA复制中具有作用，因为其ATP酶活性的抑制可导致S期停滞，其最终通过复制灾难导致癌细胞死亡。虽然RUVBL 1/2的体内药理学抑制导致适度的抗肿瘤活性，但它在NSCLC中与辐射协同作用，而不是正常细胞，这是未来临床前开发的一个有吸引力的特性。Yenerall等鉴定了RUVBL 1/2 ATP酶活性的特异性抑制剂，化合物B，并证明RUVBL 1/2 ATP酶活性是PAQosome成熟/解离所需的。化合物B通过抑制DNA复制杀死非小细胞肺癌（NSCLC）。此外，化合物B使NSCLC而不是正常细胞放射增敏，这是未来开发的有吸引力的性质。
RUVBL1 and RUVBL2 (collectively RUVBL1/2) are essential AAA+ ATPases that function as co-chaperones and have been implicated in cancer. Here we investigated the molecular and phenotypic role of RUVBL1/2 ATPase activity in non-small cell lung cancer (NSCLC). We find that RUVBL1/2 are overexpressed in NSCLC patient tumors, with high expression associated with poor survival. Utilizing a specific inhibitor of RUVBL1/2 ATPase activity, we show that RUVBL1/2 ATPase activity is necessary for the maturation or dissociation of the PAQosome, a large RUVBL1/2-dependent multiprotein complex. We also show that RUVBL1/2 have roles in DNA replication, as inhibition of its ATPase activity can cause S-phase arrest, which culminates in cancer cell death via replication catastrophe. While in vivo pharmacological inhibition of RUVBL1/2 results in modest antitumor activity, it synergizes with radiation in NSCLC, but not normal cells, an attractive property for future preclinical development. Yenerall et al. identified a specific inhibitor of RUVBL1/2 ATPase activity, compound B, and demonstrate that RUVBL1/2 ATPase activity is required for PAQosome maturation/dissociation. Compound B kills non-small cell lung cancer (NSCLC) by inhibiting DNA replication. In addition, compound B radiosensitizes NSCLC, but not normal cells, an attractive property for future development.
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影响因子：
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