Nandi Deeptashree, Cheema Pradeep Singh, Singal Aakriti, Bharti Hina, Nag Alo
Department of Biochemistry, University of Delhi, New Delhi, India.
Front Oncol. 2021 Nov 24;11:751271. doi: 10.3389/fonc.2021.751271. eCollection 2021.
The aberrant up-regulation of the oncogenic transcription factor Forkhead box M1 (FoxM1) is associated with tumor development, progression and metastasis in a myriad of carcinomas, thus establishing it as an attractive target for anticancer drug development. FoxM1 overexpression in hepatocellular carcinoma is reflective of tumor aggressiveness and recurrence, poor prognosis and low survival in patients. In our study, we have identified the antimalarial natural product, Artemisinin, to efficiently curb FoxM1 expression and activity in hepatic cancer cells, thereby exhibiting potential anticancer efficacy. Here, we demonstrated that Artemisinin considerably mitigates FoxM1 transcriptional activity by disrupting its interaction with the promoter region of its downstream targets, thereby suppressing the expression of numerous oncogenic drivers. Augmented level of FoxM1 is implicated in drug resistance of cancer cells, including hepatic tumor cells. Notably, FoxM1 overexpression rendered HCC cells poorly responsive to Artemisinin-mediated cytotoxicity while FoxM1 depletion in resistant liver cancer cells sensitized them to Artemisinin treatment, manifested in lower proliferative and growth index, drop in invasive potential and repressed expression of EMT markers with a concomitantly increased apoptosis. Moreover, Artemisinin, when used in combination with Thiostrepton, an established FoxM1 inhibitor, markedly reduced anchorage-independent growth and displayed more pronounced death in liver cancer cells. We found this effect to be evident even in the resistant HCC cells, thereby putting forth a novel combination therapy for resistant cancer patients. Altogether, our findings provide insight into the pivotal involvement of FoxM1 in the tumor suppressive activities of Artemisinin and shed light on the potential application of Artemisinin for improved therapeutic response, especially in resistant hepatic malignancies. Considering that Artemisinin compounds are in current clinical use with favorable safety profiles, the results from our study will potentiate its utility in juxtaposition with established FoxM1 inhibitors, promoting maximal therapeutic efficacy with minimal adverse effects in liver cancer patients.
致癌转录因子叉头框蛋白M1（FoxM1）的异常上调与多种癌症的肿瘤发生、进展和转移相关，因此使其成为抗癌药物开发的一个有吸引力的靶点。肝细胞癌中FoxM1的过表达反映了肿瘤的侵袭性和复发、患者预后不良及低生存率。在我们的研究中，我们已确定抗疟天然产物青蒿素能有效抑制肝癌细胞中FoxM1的表达和活性，从而展现出潜在的抗癌功效。在此，我们证明青蒿素通过破坏FoxM1与其下游靶点启动子区域的相互作用，显著减轻其转录活性，从而抑制众多致癌驱动因子的表达。FoxM1水平升高与癌细胞包括肝肿瘤细胞的耐药性有关。值得注意的是，FoxM1过表达使肝癌细胞对青蒿素介导的细胞毒性反应不佳，而耐药肝癌细胞中FoxM1的缺失使其对青蒿素治疗敏感，表现为增殖和生长指数降低、侵袭潜能下降以及上皮-间质转化标志物表达受抑制，同时凋亡增加。此外，青蒿素与已有的FoxM1抑制剂硫链丝菌素联合使用时，能显著降低肝癌细胞的非锚定依赖性生长，并在肝癌细胞中表现出更明显的细胞死亡。我们发现这种效应在耐药肝癌细胞中也很明显，从而为耐药癌症患者提出了一种新的联合治疗方法。总之，我们的研究结果深入了解了FoxM1在青蒿素肿瘤抑制活性中的关键作用，并揭示了青蒿素在改善治疗反应方面的潜在应用，特别是在耐药性肝恶性肿瘤中。鉴于青蒿素类化合物目前已在临床使用且安全性良好，我们的研究结果将增强其与已有的FoxM1抑制剂并列使用的效用，在肝癌患者中以最小的副作用促进最大的治疗效果。
