Avenhaus Alicia, Kuhn Bianca J, Velimirović Milica, Strobel Tobias D, Bulkescher Julia, Lohrey Claudia, Krijgsveld Jeroen, Hoppe-Seyler Felix, Hoppe-Seyler Karin
German Cancer Research Center (DKFZ), Molecular Therapy of Virus-Associated Cancers, Heidelberg, Germany.
Faculty of Biosciences, Heidelberg University, Heidelberg, Germany.
J Med Virol. 2025 Jun;97(6):e70434. doi: 10.1002/jmv.70434.
Improved treatment strategies for HPV-positive cancers are urgently required. The viral E6/E7 oncoproteins are essential for the proliferation of HPV-positive cancer cells and considered attractive therapeutic targets. Metformin is proposed to be repurposed for cancer therapy, but this is under controversial debate. We previously demonstrated that E6/E7 expression and the proliferation of HPV-positive cancer cells are repressed by Metformin. Here, we explore the effects of Metformin on the phenotype of HPV-positive cancer cells in detail, either applied as monotreatment or in combination with chemotherapeutic agents. We provide evidence that the downregulation of E6/E7 is not the primary mechanism underlying Metformin's growth-inhibitory effect in HPV-positive cancer cells. Specifically, compared to targeted E6/E7 repression by RNA interference (RNAi), Metformin treatment differently altered the expression of growth regulatory proteins, exerted different effects on the cell cycle, and was able to suppress growth even in the presence of E6/E7. Furthermore, we found that cancer cells pre-treated with Metformin become resistant to senescence induction by the pro-senescent chemotherapeutic agent Etoposide, likely as a secondary effect of Metformin-induced growth inhibition. Finally, depending on experimental conditions, we uncover divergent, even opposing, effects on the proliferation of HPV-positive cancer cells when Metformin is combined with Cisplatin, with p53 playing a key role in these processes. Collectively, our results show that Metformin exerts complex effects on the phenotype of HPV-positive cancer cells, which are critically influenced by experimental conditions. Our findings may also explain the discrepant results in the literature, reporting agonistic or antagonistic effects upon combining Metformin with Cisplatin.
迫切需要改进针对人乳头瘤病毒（HPV）阳性癌症的治疗策略。病毒E6/E7癌蛋白对于HPV阳性癌细胞的增殖至关重要，被认为是有吸引力的治疗靶点。有人提出将二甲双胍重新用于癌症治疗，但这一观点存在争议。我们之前证明二甲双胍可抑制HPV阳性癌细胞中E6/E7的表达及增殖。在此，我们详细探究了二甲双胍对HPV阳性癌细胞表型的影响，包括单独使用或与化疗药物联合使用的情况。我们提供的证据表明，E6/E7的下调并非二甲双胍对HPV阳性癌细胞生长抑制作用的主要机制。具体而言，与通过RNA干扰（RNAi）靶向抑制E6/E7相比，二甲双胍处理对生长调节蛋白的表达产生了不同的改变，对细胞周期产生了不同的影响，并且即使在存在E6/E7的情况下也能够抑制生长。此外，我们发现预先用二甲双胍处理的癌细胞对促衰老化疗药物依托泊苷诱导的衰老产生抗性，这可能是二甲双胍诱导生长抑制的继发效应。最后，根据实验条件，我们发现当二甲双胍与顺铂联合使用时，对HPV阳性癌细胞的增殖有不同甚至相反的影响，其中p53在这些过程中起关键作用。总体而言，我们的结果表明二甲双胍对HPV阳性癌细胞的表型产生复杂影响，这些影响受到实验条件的严重影响。我们的发现也可能解释了文献中关于二甲双胍与顺铂联合使用时产生激动或拮抗作用的不一致结果。
