The anaphase-promoting complex/cyclosome co-activator, Cdh1, is a novel target of human papillomavirus 16 E7 oncoprotein in cervical oncogenesis.

The transforming properties of the high-risk human papillomavirus (HPV) E7 oncoprotein are indispensable for driving the virus life cycle and pathogenesis. Besides inactivation of the retinoblastoma family of tumor suppressors as part of its oncogenic endeavors, E7-mediated perturbations of eminent cell cycle regulators, checkpoint proteins and proto-oncogenes are considered to be the tricks of its transformative traits. However, many such critical interactions are still unknown. In the present study, we have identified the anaphase-promoting complex/cyclosome (APC) co-activator, Cdh1, as a novel interacting partner and a degradation target of E7. We found that HPV16 E7-induced inactivation of Cdh1 promoted abnormal accumulation of multiple Cdh1 substrates. Such a mode of deregulation possibly contributes to HPV-mediated cervical oncogenesis. Our mapping studies recognized the C-terminal zinc-finger motif of E7 to associate with Cdh1 and interfere with the timely degradation of FoxM1, a bona fide Cdh1 substrate and a potent oncogene. Importantly, the E7 mutant with impaired interaction with Cdh1 exhibited defects in its ability for overriding typical cell cycle transition and oncogenic transformation, thereby validating the functional and pathological significance of the E7-Cdh1 axis during cervical carcinoma progression. Altogether, the findings from our study discover a unique nexus between E7 and APC/C-Cdh1, thereby adding to our understanding of the mechanism of E7-induced carcinogenesis and provide a promising target for the management of cervical carcinoma.

Repurposing the Pathogen Box compounds for identification of potent anti-malarials against blood stages of Plasmodium falciparum with PfUCHL3 inhibitory activity.

Malaria has endured as a global epidemic since ages and its eradication poses an immense challenge due to the complex life cycle of the causative pathogen and its tolerance to a myriad of therapeutics. PfUCHL3, a member of the ubiquitin C-terminal hydrolase (UCH) family of deubiquitinases (DUBs) is cardinal for parasite survival and emerges as a promising therapeutic target. In this quest, we employed a combination of computational and experimental approaches to identify PfUCHL3 inhibitors as novel anti-malarials. The Pathogen Box library was screened against the crystal structure of PfUCHL3 (PDB ID: 2WE6) and its human ortholog (PDB ID: 1XD3). Fifty molecules with better comparative score, bioavailability and druglikeliness were subjected to in-vitro enzyme inhibition assay and among them only two compounds effectively inhibited PfUCHL3 activity at micro molar concentrations. Both MMV676603 and MMV688704 exhibited anti-plasmodial activity by altering the parasite phenotype at late stages of the asexual life cycle and inducing the accumulation of polyubiquitinated substrates. In addition, both the compounds were non-toxic and portrayed high selectivity window for the parasite over mammalian cells. This is the first comprehensive study to demonstrate the anti-malarial efficacy of PfUCHL3 inhibitors and opens new avenues to exploit UCH family of DUBs as a promising target for the development of next generation anti-malaria therapy.

Artemisinin Mediates Its Tumor-Suppressive Activity in Hepatocellular Carcinoma Through Targeted Inhibition of FoxM1.

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.

Exploring the therapeutic potential of forkhead box O for outfoxing COVID-19.

The COVID-19 pandemic has wreaked unprecedented societal havoc worldwide. The infected individuals may present mild to severe symptoms, with nearly 20% of the confirmed patients impaired with significant complications, including multi-organ failure. Acute respiratory distress imposed by SARS-CoV-2 largely results from an aggravated cytokine storm and deregulated immune response. The forkhead box O (FoxO) transcription factors are reported to play a significant role in maintaining normal cell physiology by regulating survival, apoptosis, oxidative stress, development and maturation of T and B lymphocytes, secretion of inflammatory cytokines, etc. We propose a potent anti-inflammatory approach based on activation of the FoxO as an attractive strategy against the novel coronavirus. This regime will be focused on restoring redox and inflammatory homeostasis along with repair of the damaged tissue, activation of lymphocyte effector and memory cells. Repurposing FoxO activators as a means to alleviate the inflammatory burst following SARS-CoV-2 infection can prove immensely valuable in the ongoing pandemic and provide a reliable groundwork for enriching our repertoire of antiviral modalities for any such complication in the future. Altogether, our review highlights the possible efficacy of FoxO activation as a novel arsenal for clinical management of COVID-19.

FoxM1: Repurposing an oncogene as a biomarker.

The past few decades have witnessed a tremendous progress in understanding the biology of cancer, which has led to more comprehensive approaches for global gene expression profiling and genome-wide analysis. This has helped to determine more sophisticated prognostic and predictive signature markers for the prompt diagnosis and precise screening of cancer patients. In the search for novel biomarkers, there has been increased interest in FoxM1, an extensively studied transcription factor that encompasses most of the hallmarks of malignancy. Considering the attractive potential of this multifarious oncogene, FoxM1 has emerged as an important molecule implicated in initiation, development and progression of cancer. Bolstered with the skill to maneuver the proliferation signals, FoxM1 bestows resistance to contemporary anti-cancer therapy as well. This review sheds light on the large body of literature that has accumulated in recent years that implies that FoxM1 neoplastic functions can be used as a novel predictive, prognostic and therapeutic marker for different cancers. This assessment also highlights the key features of FoxM1 that can be effectively harnessed to establish FoxM1 as a strong biomarker in diagnosis and treatment of cancer.