Park Soyeong, Auyeung Andrew, Lee Denis L, Lambert Paul F, Carchman Evie H, Sherer Nathan M
McArdle Laboratory for Cancer Research, Deptartment of Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA.
Institute for Molecular Virology, University of Wisconsin-Madison, Madison, WI 53706, USA.
Cancers (Basel). 2021 Feb 24;13(5):949. doi: 10.3390/cancers13050949.
High-risk human papillomavirus strain 16 (HPV16) causes oral and anogenital cancers through the activities of two viral oncoproteins, E6 and E7, that dysregulate the host p53 and pRb tumor suppressor pathways, respectively. The maintenance of HPV16-positive cancers requires constitutive expression of E6 and E7. Therefore, inactivating these proteins could provide the basis for an anticancer therapy. Herein we demonstrate that a subset of aspartyl protease inhibitor drugs currently used to treat HIV/AIDS cause marked reductions in HPV16 E6 and E7 protein levels using two independent cell culture models: HPV16-transformed CaSki cervical cancer cells and NIKS16 organotypic raft cultures (a 3-D HPV16-positive model of epithelial pre-cancer). Treatment of CaSki cells with some (lopinavir, ritonavir, nelfinavir, and saquinavir) but not other (indinavir and atazanavir) protease inhibitors reduced E6 and E7 protein levels, correlating with increased p53 protein levels and decreased cell viability. Long-term (>7 day) treatment of HPV16-positive NIKS16 raft cultures with saquinavir caused epithelial atrophy with no discernible effects on HPV-negative rafts, demonstrating selectivity. Saquinavir also reduced HPV16's effects on markers of the cellular autophagy pathway in NIKS16 rafts, a hallmark of HPV-driven pre-cancers. Taken together, these data suggest HIV-1 protease inhibitors be studied further in the context of treating or preventing HPV16-positive cancers.
高危型人乳头瘤病毒16型（HPV16）通过两种病毒癌蛋白E6和E7的作用引发口腔癌和肛门生殖器癌，这两种蛋白分别会破坏宿主的p53和pRb肿瘤抑制途径。HPV16阳性癌症的维持需要E6和E7的持续表达。因此，使这些蛋白失活可为抗癌治疗提供依据。在此，我们使用两种独立的细胞培养模型证明，目前用于治疗HIV/AIDS的一部分天冬氨酸蛋白酶抑制剂药物可使HPV16 E6和E7蛋白水平显著降低：HPV16转化的CaSki宫颈癌细胞和NIKS16器官型筏培养物（一种三维HPV16阳性上皮癌前病变模型）。用某些（洛匹那韦、利托那韦、奈非那韦和沙奎那韦）而非其他（茚地那韦和阿扎那韦）蛋白酶抑制剂处理CaSki细胞可降低E6和E7蛋白水平，这与p53蛋白水平升高和细胞活力降低相关。用沙奎那韦对HPV16阳性的NIKS16筏培养物进行长期（>7天）处理会导致上皮萎缩，而对HPV阴性筏培养物没有明显影响，显示出选择性。沙奎那韦还降低了HPV16对NIKS16筏中细胞自噬途径标志物的影响，这是HPV驱动的癌前病变的一个标志。综上所述，这些数据表明，在治疗或预防HPV16阳性癌症方面，应进一步研究HIV-1蛋白酶抑制剂。
