Amsterdam UMC location Vrije Universiteit Amsterdam, Medical Oncology, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands.
ORCA Therapeutics BV, Onderwijsboulevard 225, 5223 DE 's Hertogenbosch, The Netherlands.
Int J Mol Sci. 2022 Dec 6;23(23):15430. doi: 10.3390/ijms232315430.
Oncolytic adenoviruses are promising new anticancer agents. To realize their full anticancer potential, they are being engineered to express therapeutic payloads. Tumor suppressor p53 function contributes to oncolytic adenovirus activity. Many cancer cells carry an intact gene but express p53 inhibitors that compromise p53 function. Therefore, we hypothesized that oncolytic adenoviruses could be made more effective by suppressing p53 inhibitors in selected cancer cells. To investigate this concept, we attenuated the expression of the established p53 inhibitor synoviolin (SYVN1) in A549 lung cancer cells by RNA interference. Silencing inhibited p53 degradation, thereby increasing p53 activity, and promoted adenovirus-induced A549 cell death. Based on these observations, we constructed a new oncolytic adenovirus that expresses a short hairpin RNA against . This virus killed A549 cells more effectively in vitro and inhibited A549 xenograft tumor growth in vivo. Surprisingly, increased susceptibility to adenovirus-mediated cell killing by silencing was also observed in A549 knockout cells. Hence, while the mechanism of SYVN1-mediated inhibition of adenovirus replication is not fully understood, our results clearly show that RNA interference technology can be exploited to design more potent oncolytic adenoviruses.
溶瘤腺病毒是很有前途的新型抗癌药物。为了充分发挥其抗癌潜力，人们对其进行了工程改造，以表达治疗性有效载荷。肿瘤抑制因子 p53 的功能有助于溶瘤腺病毒的活性。许多癌细胞携带有完整的 基因，但表达抑制 p53 功能的 p53 抑制剂。因此，我们假设通过抑制选定癌细胞中的 p53 抑制剂，可以使溶瘤腺病毒更有效。为了研究这一概念，我们通过 RNA 干扰减弱了肺癌细胞 A549 中已建立的 p53 抑制剂 synoviolin (SYVN1) 的表达。沉默抑制了 p53 的降解，从而增加了 p53 的活性，并促进了腺病毒诱导的 A549 细胞死亡。基于这些观察结果，我们构建了一种表达针对 的短发夹 RNA 的新型溶瘤腺病毒。该病毒在体外更有效地杀死 A549 细胞，并抑制 A549 异种移植肿瘤在体内的生长。令人惊讶的是，沉默也增加了 A549 基因敲除细胞对腺病毒介导的细胞杀伤的敏感性。因此，虽然 SYVN1 介导的腺病毒复制抑制机制尚未完全阐明，但我们的结果清楚地表明，RNA 干扰技术可用于设计更有效的溶瘤腺病毒。
