Sensitisation to mitoxantrone-induced apoptosis by the oncolytic adenovirus AdΔΔ through Bcl-2-dependent attenuation of autophagy
Sensitisation to mitoxantrone-induced apoptosis by the oncolytic adenovirus AdΔΔ through Bcl-2-dependent attenuation of autophagy
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DOI：
10.1038/s41389-017-0020-8
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发表时间：
2018-01-01
期刊：
影响因子：
6.2
通讯作者：
Hallden, Gunnel
中科院分区：
文献类型：
--
作者：
Aguirre-Hernandez, Carmen;Maya-Pineda, Hector;Hallden, Gunnel
抗凋亡基因Bcl2在人类恶性肿瘤细胞中经常被激活，以促进细胞存活和抑制细胞死亡。在功能性的Bcl2同源物E1B19K中缺失的复制选择性溶瘤腺病毒可以与诱导凋亡的化疗药物协同作用，包括治疗前列腺癌的米托蒽醌。在这里，我们证明了我们之前产生的溶瘤突变体Ad Delta(E1B19K-和E1ACR2-缺失)在药物敏感的22Rv1以及药物不敏感的PC3和PC3M前列腺癌细胞中都导致了强大的协同凋亡细胞死亡。协同杀伤依赖于Bcl2的表达，并被Bcl2基因敲除，从而导致自噬途径的激活。MITOX-ANTRONE诱导的自噬与AdDelta-Delta感染联合作用减弱，导致细胞凋亡增加。单独表达病毒E1A12S蛋白可模拟AdDelta与米托蒽醌的协同作用，而完整的野生型病毒(Ad5)则不起作用。ATG7基因敲除和氯喹对自噬的早期和晚期抑制作用与AdDelta Delta类似，米托蒽醌可促进细胞的凋亡。这些发现揭示了目前尚不清楚的E1B19K缺失溶瘤腺病毒的作用以及Bcl2在协同杀伤细胞中的中心作用。这项研究表明，具有功能性Bcl-2表达的癌症可能会选择性地通过Ad Delta Delta重新对药物敏感。
Anti-apoptotic Bcl-2 is frequently activated in human malignant cells to promote cell survival and inhibit cell death. Replication-selective oncolytic adenoviruses deleted in the functional Bcl-2 homologue E1B19K potently synergise with apoptosis-inducing chemotherapeutic drugs, including mitoxantrone for prostate cancer. Here, we demonstrate that our previously generated oncolytic mutant Ad Delta Delta (E1B19K- and E1ACR2-deleted) caused potent synergistic apoptotic cell death in both drug-sensitive 22Rv1, and drug-insensitive PC3 and PC3M prostate cancer cells. The synergistic cell killing was dependent on Bcl-2 expression and was prevented by Bcl-2 knockdown, which led to activation of the autophagy pathway. Mitoxantrone-induced autophagy, which was decreased in combination with Ad Delta Delta-infection resulting in increased apoptosis. Expression of the viral E1A12S protein alone mimicked the synergistic effects with Ad Delta Delta in combination with mitoxantrone while intact wild-type virus (Ad5) had no effect. Early and latestage inhibition of autophagy by Atg7 knockdown and chloroquine respectively, promoted apoptotic cell killing with mitoxantrone similar to Ad Delta Delta. These findings revealed currently unexplored actions of E1B19K deleted oncolytic adenoviruses and the central role of Bcl-2 in the synergistic cell killing. This study suggests that cancers with functional Bcl-2 expression may be selectively re-sensitised to drugs by Ad Delta Delta.