Effects of the antifungal agent ciclopirox in HPV-positive cancer cells: Repression of viral E6/E7 oncogene expression and induction of senescence and apoptosis
Effects of the antifungal agent ciclopirox in HPV-positive cancer cells: Repression of viral E6/E7 oncogene expression and induction of senescence and apoptosis
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DOI：
10.1002/ijc.32709
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发表时间：
2020-01-15
影响因子：
6.4
通讯作者：
Hoppe-Seyler, Felix
中科院分区：
文献类型：
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作者：
Braun, Julia A.;Herrmann, Anja L.;Hoppe-Seyler, Felix
人乳头瘤病毒(HPV)阳性癌细胞的恶性生长依赖于病毒E6/E7癌基因的持续表达。在这里，我们研究了缺铁对HPV阳性宫颈癌细胞表型的影响。我们发现，铁络合剂，如外用抗真菌药物环丙吡喃(CPX)，在转录和蛋白水平上都能强烈抑制HPVE6/E7癌基因的表达。CPX通过诱导细胞衰老有效地阻断了HPV阳性癌细胞的增殖。虽然活跃的mTOR信号被认为是细胞对多种延年剂的衰老反应的关键，但CPX诱导的衰老发生在mTOR信号严重受损的情况下。长时间的CPX治疗会导致非P53依赖的Caspase-3/7激活并诱导细胞凋亡。CPX还通过诱导细胞凋亡在低氧条件下消除HPV阳性癌细胞。综上所述，这些结果表明，缺铁在HPV阳性的癌细胞中发挥着深刻的抗病毒和抗增殖作用，并表明铁络合剂，如CPX，在常氧和低氧环境中都具有作为HPV抑制、衰老和促凋亡的治疗潜力。
The malignant growth of human papillomavirus (HPV)-positive cancer cells is dependent on the continuous expression of the viral E6/E7 oncogenes. Here, we examined the effects of iron deprivation on the phenotype of HPV-positive cervical cancer cells. We found that iron chelators, such as the topical antifungal agent ciclopirox (CPX), strongly repress HPV E6/E7 oncogene expression, both at the transcript and protein level. CPX efficiently blocks the proliferation of HPV-positive cancer cells by inducing cellular senescence. Although active mTOR signaling is considered to be critical for the cellular senescence response towards a variety of prosenescent agents, CPX-induced senescence occurs under conditions of severely impaired mTOR signaling. Prolonged CPX treatment leads to p53-independent Caspase-3/7 activation and induction of apoptosis. CPX also eliminates HPV-positive cancer cells under hypoxic conditions through induction of apoptosis. Taken together, these results show that iron deprivation exerts profound antiviral and antiproliferative effects in HPV-positive cancer cells and suggest that iron chelators, such as CPX, possess therapeutic potential as HPV-inhibitory, prosenescent and proapoptotic agents in both normoxic and hypoxic environments.