Chlorpromazine affects glioblastoma bioenergetics by interfering with pyruvate kinase M2.

Glioblastoma (GBM) is the most frequent and lethal brain tumor, whose therapeutic outcome - only partially effective with current schemes - places this disease among the unmet medical needs, and effective therapeutic approaches are urgently required. In our attempts to identify repositionable drugs in glioblastoma therapy, we identified the neuroleptic drug chlorpromazine (CPZ) as a very promising compound. Here we aimed to further unveil the mode of action of this drug. We performed a supervised recognition of the signal transduction pathways potentially influenced by CPZ via Reverse-Phase Protein microArrays (RPPA) and carried out an Activity-Based Protein Profiling (ABPP) followed by Mass Spectrometry (MS) analysis to possibly identify cellular factors targeted by the drug. Indeed, the glycolytic enzyme PKM2 was identified as one of the major targets of CPZ. Furthermore, using the Seahorse platform, we analyzed the bioenergetics changes induced by the drug. Consistent with the ability of CPZ to target PKM2, we detected relevant changes in GBM energy metabolism, possibly attributable to the drug's ability to inhibit the oncogenic properties of PKM2. RPE-1 non-cancer neuroepithelial cells appeared less responsive to the drug. PKM2 silencing reduced the effects of CPZ. 3D modeling showed that CPZ interacts with PKM2 tetramer in the same region involved in binding other known activators. The effect of CPZ can be epitomized as an inhibition of the Warburg effect and thus malignancy in GBM cells, while sparing RPE-1 cells. These preclinical data enforce the rationale that allowed us to investigate the role of CPZ in GBM treatment in a recent multicenter Phase II clinical trial.

Digital twin models of replicative ground stones: insight into simulating usage of Upper Paleolithic tools.

This work presents the first attempt to create a physics-based digital twin model for predictive analysis of damage evolution during the use of ground stone tools (GSTs) in transformative tasks, encompassing the processing of raw resources for nutritional and non-alimentary purposes. The proposed methodology introduces a digital twin of the GSTs developed from 3D models generated using a photogrammetric technique based on Structure-from-Motion and Multi-View Stereo reconstruction. These models serve as the foundation for the development of the finite element (FE)-based digital twin model of the GSTs that exploits a contact formulation and the phase-field approach to simulate tool damage during pounding and grinding tasks. Defining the initial relative positions of the stones, their mechanical behaviour, and controlling the movement of the active stone in a way as close as possible to the real one, the digital twin model has been devised to evaluate how the surface damage is affected by perturbations in the loading conditions. The simulated damage is compared with the surface traces observed from experiments. The developed digital twin model aims at demonstrating its potentials for the GSTs investigations, as a supporting tool for experiments and for simulated tests on the archaeological records.

Close-range photogrammetry reveals morphometric changes on replicative ground stones.

The pursuit of a quantitative approach to functional analysis of stone tools is an ongoing endeavour for traceologists. Technological advancements in 3D imaging techniques, such as photogrammetry/3D scanners, CT scanning, 3D digital microscopy, confocal microscopy, AFM and FEG-SEM and micro-topographical scanning, have greatly facilitated the detailed capturing of the geometry and surface texture at multiple levels of observation, from the object-scale to the nano-scale. However, while such technological innovations have predominantly focused on flaked assemblages, ground stone tools have only recently begun to receive due attention, and a standardised protocol for their study is yet to be established. In order to comprehend the function(s) of these tools, analytical techniques that enable a 3D visualisation of the entire item and the wear affecting the used surfaces have proven to be of great support. To this end, an analytical procedure was developed and tested on slabs and pebbles in order to replicate the use-wear traces observed on Upper Palaeolithic tools. The purpose was to assemble a site-specific reference collection tailored on the artefacts from the cultural level III of the Brînzeni I cave in north-west Moldova. Experimental replicas were used to treat different plant organs during controlled sequential experiments. The present article reports on the analysis based on photogrammetric data acquired during two stages of replicative usage. We tested multiple acquisition setups and elaborations to assess the geometry modification and the surface depletion. By exploring various acquisition strategies, a critical evaluation of potential sources of bias in data collection and subsequent elaboration were performed, and the methodology was accordingly adjusted thereby enhancing the reliability and reproducibility of the results. This study highlights the importance of carefully considering the acquisition strategy in archaeological related research to ensure accurate analyses and to validate robust interpretation.

Shaping Silver Nanoparticles' Size through the Carrier Composition: Synthesis and Antimicrobial Activity.

The increasing resistance of bacteria to conventional antibiotics represents a severe global emergency for human health. The broad-spectrum antibacterial activity of silver has been known for a long time, and silver at the nanoscale shows enhanced antibacterial activity. This has prompted research into the development of silver-based nanomaterials for applications in clinical settings. In this work, the synthesis of three different silver nanoparticles (AgNPs) hybrids using both organic and inorganic supports with intrinsic antibacterial properties is described. The tuning of the AgNPs' shape and size according to the type of bioactive support was also investigated. Specifically, the commercially available sulfated cellulose nanocrystal (CNC), the salicylic acid functionalized reduced graphene oxide (rGO-SA), and the commercially available titanium dioxide (TiO2) were chosen as organic (CNC, rGO-SA) and inorganic (TiO2) supports. Then, the antimicrobial activity of the AgNP composites was assessed on clinically relevant multi-drug-resistant bacteria and the fungus Candida albicans. The results show how the formation of Ag nanoparticles on the selected supports provides the resulting composite materials with an effective antibacterial activity.

Efficacy and safety of chlorpromazine as an adjuvant therapy for glioblastoma in patients with unmethylated MGMT gene promoter: RACTAC, a phase II multicenter trial.

Introduction: Drug repurposing is a promising strategy to develop new treatments for glioblastoma. In this phase II clinical trial, we evaluated the addition of chlorpromazine to temozolomide in the adjuvant phase of the standard first-line therapeutic protocol in patients with unmethylated MGMT gene promoter. Methods: This was a multicenter phase II single-arm clinical trial. The experimental procedure involved the combination of CPZ with standard treatment with TMZ in the adjuvant phase of the Stupp protocol in newly-diagnosed GBM patients carrying an unmethylated MGMT gene promoter. Progression-free survival was the primary endpoint. Secondary endpoints were overall survival and toxicity. Results: Forty-one patients were evaluated. Twenty patients (48.7%) completed 6 cycles of treatment with TMZ+CPZ. At 6 months, 27 patients (65.8%) were without progression, achieving the primary endpoint. Median PFS was 8.0 months (95% CI: 7.0-9.0). Median OS was 15.0 months (95% CI: 13.1-16.9). Adverse events led to reduction or interruption of CPZ dosage in 4 patients (9.7%). Discussion: The addition of CPZ to standard TMZ in the first-line treatment of GBM patients with unmethylated MGMT gene promoter was safe and led to a longer PFS than expected in this population of patients. These findings provide proof-of-concept for the potential of adding CPZ to standard TMZ treatment in GBM patients with unmethylated MGMT gene promoter. Clinical trial registration: https://clinicaltrials.gov/study/NCT04224441, identifier NCT04224441.

Molecular Biology in Glioblastoma Multiforme Treatment.

Glioblastoma (GBM, grade IV astrocytoma), the most frequently occurring primary brain tumor, presents unique challenges to therapy due to its location, aggressive biological behavior, and diffuse infiltrative growth, thus contributing to having disproportionately high morbidity and mortality [...].

Deciphering specific miRNAs in brain tumors: a 5-miRNA signature in glioblastoma.

MicroRNAs are endogenous non-coding RNAs with a marked impact on the development and progression of brain tumors. However, they commonly share different expression patterns in other types of tumors, thereby exhibiting lack of tissue specificity. Here, an integrative holistic analysis of microarray data is established for deciphering dysregulated miRNAs in glioblastoma, distinguishing them from eight other CNS tumors. The identification of dysregulated miRNAs was performed in a pool of 176 patients, 118 of which diagnosed with glioblastoma. Dysregulated miRNAs commonly expressed in glioblastoma were then discriminated from those co-expressed in other CNS tumors and further characterized. Overall, 21 miRNAs were found to be commonly dysregulated in glioblastoma. Notwithstanding, 16 miRNAs also exhibited a differential expression in at least one other CNS tumor. The remaining 5, specifically, hsa-miR-21-3p, hsa-miR-338-5p, hsa-miR-485-5p, hsa-miR-491-5p and hsa-miR-1290, were solely associated to glioblastoma. This signature is in-depth characterized, with the spotlight on tumor progression, invasion and patient survival. These five endogenous molecules, differentially expressed in glioblastoma, are thus suggested as potential therapeutic targets, modulating several genes involved in major signalling pathways, including MAPK/ERK, calcium, PI3K/AKT, mTOR and Wnt. In summary, these findings lay a foundation for further research on the expression and function of specific patterns of miRNAs expression in glioblastoma, providing reference for potential novel targets.

Tackling the Behavior of Cancer Cells: Molecular Bases for Repurposing Antipsychotic Drugs in the Treatment of Glioblastoma.

Glioblastoma (GBM) is associated with a very dismal prognosis, and current therapeutic options still retain an overall unsatisfactorily efficacy in clinical practice. Therefore, novel therapeutic approaches and effective medications are highly needed. Since the development of new drugs is an extremely long, complex and expensive process, researchers and clinicians are increasingly considering drug repositioning/repurposing as a valid alternative to the standard research process. Drug repurposing is also under active investigation in GBM therapy, since a wide range of noncancer and cancer therapeutics have been proposed or investigated in clinical trials. Among these, a remarkable role is played by the antipsychotic drugs, thanks to some still partially unexplored, interesting features of these agents. Indeed, antipsychotic drugs have been described to interfere at variable incisiveness with most hallmarks of cancer. In this review, we analyze the effects of antipsychotics in oncology and how these drugs can interfere with the hallmarks of cancer in GBM. Overall, according to available evidence, mostly at the preclinical level, it is possible to speculate that repurposing of antipsychotics in GBM therapy might contribute to providing potentially effective and inexpensive therapies for patients with this disease.

Chlorpromazine induces cytotoxic autophagy in glioblastoma cells via endoplasmic reticulum stress and unfolded protein response.

BACKGROUND: Glioblastoma (GBM; grade IV glioma) is characterized by a very short overall survival time and extremely low 5-year survival rates. We intend to promote experimental and clinical research on rationale and scientifically driven drug repurposing. This may represent a safe and often inexpensive way to propose novel pharmacological approaches to GBM. Our precedent work describes the role of chlorpromazine (CPZ) in hindering malignant features of GBM. Here, we investigate in greater detail the molecular mechanisms at the basis of the effect of CPZ on GBM cells. METHODS: We employed proteomics platforms, i.e., activity-based protein profiling plus mass spectrometry, to identify potential cellular targets of the drug. Then, by means of established molecular and cellular biology techniques, we assessed the effects of this drug on GBM cell metabolic and survival pathways. RESULTS: The experimental output indicated as putative targets of CPZ several of factors implicated in endoplasmic reticulum (ER) stress, with consequent unfolded protein response (UPR). Such a perturbation culminated in a noticeable reactive oxygen species generation and intense autophagic response that resulted in cytotoxic and abortive effects for six GBM cell lines, three of which growing as neurospheres, while it appeared cytoprotective for the RPE-1 human non-cancer neuro-ectodermal cell line. CONCLUSIONS: This discrepancy could be central in explaining the lethal effects of the drug on GBM cells and the relatively scarce cytotoxicity toward normal tissues attributed to this compound. The data presented here offer support to the multicenter phase II clinical trial we have undertaken, which consists of the addition of CPZ to first-line treatment of GBM patients carrying a hypo- or un-methylated MGMT gene, i.e. those characterized by intrinsic resistance to temozolomide.

Anticancer Properties of the Antipsychotic Drug Chlorpromazine and Its Synergism With Temozolomide in Restraining Human Glioblastoma Proliferation In Vitro.

The extremely poor prognosis of patients affected by glioblastoma (GBM, grade IV glioma) prompts the search for new and more effective therapies. In this regard, drug repurposing or repositioning can represent a safe, swift, and inexpensive way to bring novel pharmacological approaches from bench to bedside. Chlorpromazine, a medication used since six decades for the therapy of psychiatric disorders, shows in vitro several features that make it eligible for repositioning in cancer therapy. Using six GBM cell lines, three of which growing as patient-derived neurospheres and displaying stem-like properties, we found that chlorpromazine was able to inhibit viability in an apoptosis-independent way, induce hyperdiploidy, reduce cloning efficiency as well as neurosphere formation and downregulate the expression of stemness genes in all these cell lines. Notably, chlorpromazine synergized with temozolomide, the first-line therapeutic in GBM patients, in hindering GBM cell viability, and both drugs strongly cooperated in reducing cloning efficiency and inducing cell death in vitro for all the GBM cell lines assayed. These results prompted us to start a Phase II clinical trial on GBM patients (EudraCT # 2019-001988-75; ClinicalTrials.gov Identifier: NCT04224441) by adding chlorpromazine to temozolomide in the adjuvant phase of the standard first-line therapeutic protocol.

Physical Interaction between HPV16E7 and the Actin-Binding Protein Gelsolin Regulates Epithelial-Mesenchymal Transition via HIPPO-YAP Axis.

Human papillomavirus 16 (HPV16) exhibits a strong oncogenic potential mainly in cervical, anogenital and oropharyngeal cancers. The E6 and E7 viral oncoproteins, acting via specific interactions with host cellular targets, are required for cell transformation and maintenance of the transformed phenotype as well. We previously demonstrated that HPV16E7 interacts with the actin-binding protein gelsolin, involved in cytoskeletal F-actin dynamics. Herein, we provide evidence that the E7/gelsolin interaction promotes the cytoskeleton rearrangement leading to epithelial-mesenchymal transition-linked morphological and transcriptional changes. E7-mediated cytoskeletal actin remodeling induces the HIPPO pathway by promoting the cytoplasmic retention of inactive P-YAP. These results suggest that YAP could play a role in the "de-differentiation" process underlying the acquisition of a more aggressive phenotype in HPV16-transformed cells. A deeper comprehension of the multifaceted mechanisms elicited by the HPV infection is vital for providing novel strategies to block the biological and clinical features of virus-related cancers.

Drug repurposing against COVID-19: focus on anticancer agents.

BACKGROUND: The very limited time allowed to face the COVID-19 pandemic poses a pressing challenge to find proper therapeutic approaches. However, synthesis and full investigation from preclinical studies to phase III trials of new medications is a time-consuming procedure, and not viable in a global emergency, such as the one we are facing. MAIN BODY: Drug repurposing/repositioning, a strategy effectively employed in cancer treatment, can represent a valid alternative. Most drugs considered for repurposing/repositioning in the therapy of the COVID-19 outbreak are commercially available and their dosage and toxicity in humans is well known, due to years (or even decades) of clinical use. This can allow their fast-track evaluation in phase II-III clinical trials, or even within straightforward compassionate use. Several drugs being re-considered for COVID-19 therapy are or have been used in cancer therapy. Indeed, virus-infected cells are pushed to enhance the synthesis of nucleic acids, protein and lipid synthesis and boost their energy metabolism, in order to comply to the "viral program". Indeed, the same features are seen in cancer cells, making it likely that drugs interfering with specific cancer cell pathways may be effective as well in defeating viral replication. SHORT CONCLUSION: To our knowledge, cancer drugs potentially suitable for facing SARS-CoV-2 infection have not been carefully reviewed. We present here a comprehensive analysis of available information on potential candidate cancer drugs that can be repurposed for the treatment of COIVD-19.

Repurposing chlorpromazine in the treatment of glioblastoma multiforme: analysis of literature and forthcoming steps.

BACKGROUND: Glioblastoma multiforme is a CNS cancer characterized by diffuse infiltrative growth, aggressive clinical behavior and very poor prognosis. The state-of-art clinical approach to this disease consists of surgical resection followed by radiotherapy plus concurrent and adjuvant chemotherapy with temozolomide. Tumor recurrence occurs in virtually all cases, therefore, despite any treatment, the median survival is very low (14.6 months), which makes the approach to these patients a challenging clinical issue. MAIN BODY: The escalating costs and times required for new medications to reach the bedside make repurposing or repositioning of old drugs, when scientific bases allow their use in other pathologies, an appealing strategy. Here, we analyze a number of literature data concerning the antipsychotic chlorpromazine, the founder of the phenothiazines class of drugs, a medication widely used in the clinics for approximately 60 years. The drug exerts its effects on psychiatric patients by interfering with the dopamine receptor D2, although more recent pharmacodynamics studies ascribe chlorpromazine a series of biological effects on cancer cells, all converging in hindering also glioblastoma survival capabilities. SHORT CONCLUSIONS: On these bases, and assisted by the information on the well-established chlorpromazine toxicity and dosage in humans, we designed a Phase II clinical trial involving the combination of chlorpromazine with the standard treatment, temozolomide, in the adjuvant phase of the therapeutic protocol. Patients displaying hypo-methylation of the MGMT gene, and thus intrinsically resistant to temozolomide, will be enrolled. The endpoints of this study are the analysis of toxicity and clinical activity, as evaluated in terms of Progression-Free Survival, of the association of chlorpromazine with the first-line treatment for this very serious form of cancer.

The influence of patient sex on clinical approaches to malignant glioma.

Gliomas are tumors that originate from the glial tissue, thus involving the central nervous system with varying degrees of malignancy. The most aggressive and frequent form is glioblastoma multiforme, a disease characterized by resistance to therapies, frequent recurrences, and extremely poor median survival time. Data on overall glioma case studies demonstrate clear sex disparities regarding incidence, prognosis, drug toxicity, clinical outcome, and, recently, prediction of therapeutic response. In this study, we analyze data in the literature regarding malignant glioma, mainly glioblastoma multiforme, focusing on epidemiological and clinical evaluations. Less discussed issues, such as the role of viral infections, energy metabolism, and predictive aspects concerning the possible use of dedicated therapeutic approaches for male or female patients, will be reported together with different estimated pathogenetic mechanisms underlying astrocyte transformation and glioma chemosensitivity. In this era, where personalized/precision medicine is the most important driver for targeted cancer therapies, the lines of evidence discussed herein strongly suggest that clinical approaches to malignant glioma should consider the patient's sex. Furthermore, retrospectively revising previous clinical studies considering patient sex as a crucial variable is recommended.

The small molecule SI113 hinders epithelial-to-mesenchymal transition and subverts cytoskeletal organization in human cancer cells.

The small molecule SI113 is an inhibitor of the kinase activity of SGK1, a key biological regulator acting on the PI3K/mTOR signal transduction pathway. Several studies demonstrate that this compound is able to strongly restrain cancer growth in vitro and in vivo, alone or in associative antineoplastic treatments, being able to elicit an autophagic response, either cytotoxic or cytoprotective. To elucidate more exhaustively the molecular mechanisms targeted by SI113, we performed activity-based protein profiling (ABPP) proteomic analysis using a kinase enrichment procedure. This technique allowed the identification via mass spectrometry of novel targets of this compound, most of them involved in functions concerning cell motility and cytoskeletal architecture. Using a glioblastoma multiforme, hepatocarcinoma and colorectal carcinoma cell line, we recognized an inhibitory effect of SI113 on cell migration, invading, and epithelial-to-mesenchymal transition. In addition, these cancer cells, when exposed to this compound, showed a remarkable subversion of the cytoskeletal architecture characterized by F-actin destabilization, phospho-FAK delocalization, and tubulin depolimerization. These results were definitely concordant in attributing to SI113 a key role in hindering cancer cell malignancy and, due to its negligible in vivo toxicity, can sustain performing a Phase I clinical trial to employ this drug in associative cancer therapy.

The kinase inhibitor SI113 induces autophagy and synergizes with quinacrine in hindering the growth of human glioblastoma multiforme cells.

BACKGROUND: Glioblastoma multiforme (GBM), due to its location, aggressiveness, heterogeneity and infiltrative growth, is characterized by an exceptionally dismal clinical outcome. The small molecule SI113, recently identified as a SGK1 inhibitor, has proven to be effective in restraining GBM growth in vitro and in vivo, showing also encouraging results when employed in combination with other antineoplastic drugs or radiotherapy. Our aim was to explore the pharmacological features of SI113 in GBM cells in order to elucidate the pivotal molecular pathways affected by the drug. Such knowledge would be of invaluable help in conceiving a rational offensive toward GBM. METHODS: We employed GBM cell lines, either established or primary (neurospheres), and used a Reverse-Phase Protein Arrays (RPPA) platform to assess the effect of SI113 upon 114 protein factors whose post-translational modifications are associated with activation or repression of specific signal transduction cascades. RESULTS: SI113 strongly affected the PI3K/mTOR pathway, evoking a pro-survival autophagic response in neurospheres. These results suggested the use of SI113 coupled, for maximum efficiency, with autophagy inhibitors. Indeed, the association of SI113 with an autophagy inhibitor, the antimalarial drug quinacrine, induced a strong synergistic effect in inhibiting GBM growth properties in all the cells tested, including neurospheres. CONCLUSIONS: RPPA clearly identified the molecular pathways influenced by SI113 in GBM cells, highlighting their vulnerability when the drug was administered in association with autophagy inhibitors, providing a strong molecular rationale for testing SI113 in clinical trials in associative GBM therapy.

Advances in Carbon Based Nanomaterials for Bio-Medical Applications.

The unique mechanical, electrical, thermal, chemical and optical properties of carbon based nanomaterials (CBNs) like: Fullerenes, Graphene, Carbon nanotubes, and their derivatives made them widely used materials for various applications including biomedicine. Few recent applications of the CBNs in biomedicine include: cancer therapy, targeted drug delivery, bio-sensing, cell and tissue imaging and regenerative medicine. However, functionalization renders the toxicity of CBNs and makes them soluble in several solvents including water, which is required for biomedical applications. Hence, this review represents the complete study of development in nanomaterials of carbon for biomedical uses. Especially, CBNs as the vehicles for delivering the drug in carbon nanomaterials is described in particular. The computational modeling approaches of various CBNs are also addressed. Furthermore, prospectus, issues and possible challenges of this rapidly developing field are highlighted.

Drug repurposing for the treatment of glioblastoma multiforme.

BACKGROUND: Glioblastoma Multiforme is the deadliest type of brain tumor and is characterized by very poor prognosis with a limited overall survival. Current optimal therapeutic approach has essentially remained unchanged for more than a decade, consisting in maximal surgical resection followed by radiotherapy plus temozolomide. MAIN BODY: Such a dismal patient outcome represents a compelling need for innovative and effective therapeutic approaches. Given the development of new drugs is a process presently characterized by an immense increase in costs and development time, drug repositioning, finding new uses for existing approved drugs or drug repurposing, re-use of old drugs when novel molecular findings make them attractive again, are gaining significance in clinical pharmacology, since it allows faster and less expensive delivery of potentially useful drugs from the bench to the bedside. This is quite evident in glioblastoma, where a number of old drugs is now considered for clinical use, often in association with the first-line therapeutic intervention. Interestingly, most of these medications are, or have been, widely employed for decades in non-neoplastic pathologies without relevant side effects. Now, the refinement of their molecular mechanism(s) of action through up-to-date technologies is paving the way for their use in the therapeutic approach of glioblastoma as well as other cancer types. SHORT CONCLUSION: The spiraling costs of new antineoplastic drugs and the long time required for them to reach the market demands a profoundly different approach to keep lifesaving therapies affordable for cancer patients. In this context, repurposing can represent a relatively inexpensive, safe and fast approach to glioblastoma treatment. To this end, pros and cons must be accurately considered.

The small molecule SI113 synergizes with mitotic spindle poisons in arresting the growth of human glioblastoma multiforme.

Glioblastoma multiforme (GBM) is the deadliest brain tumor. State-of-art GBM therapy often fails to ensure control of a disease characterized by high frequency of recurrences and progression. In search for novel therapeutic approaches, we assayed the effect of compounds from a cancer drug library on the ADF GBM cell line, establishing their elevated sensitivity to mitotic spindle poisons. Our previous work showed that the effectiveness of the spindle poison paclitaxel in inhibiting cancer cell growth was dependent on the expression of RANBP1, a regulatory target of the serine/threonine kinase SGK1. Recently, we developed the small molecule SI113 to inhibit SGK1 activity. Therefore, we explored the outcome of the association between SI113 and selected spindle poisons, finding that these drugs generated a synergistic cytotoxic effect in GBM cells, drastically reducing their viability and clonogenic capabilities in vitro, as well as inhibiting tumor growth in vivo. We also defined the molecular bases of such a synergistic effect. Because SI113 displays low systemic toxicity, yet strong activity in potentiating the effect of radiotherapy in GBM cells, we believe that this drug could be a strong candidate for clinical trials, with the aim to add it to the current GBM therapeutic approaches.

Interaction between the human papillomavirus 16 E7 oncoprotein and gelsolin ignites cancer cell motility and invasiveness.

The viral oncoprotein E7 from the "high-risk" Human Papillomavirus 16 (HPV16) strain is able, when expressed in human keratinocytes, to physically interact with the actin severing protein gelsolin (GSN). In a previous work it has been suggested that this protein-protein interaction can hinder GSN severing function, thus leading to actin network remodeling. In the present work we investigated the possible implications of this molecular interaction in cancer cell metastatic potential by analyzing two different human CC cell lines characterized by low or high expression levels of HPV16 DNA (SiHa and CaSki, respectively). In addition, a HPV-null CC cell line (C-33A), transfected in order to express the HPV16 E7 oncoprotein as well as two different deletion mutants, was also analyzed. We found that HPV16 E7 expression level was directly related with cervical cancer migration and invasion capabilities and that these HPV16 E7-related features were associated with Epithelial to Mesenchymal Transition (EMT) processes. These effects appeared as strictly attributable to the physical interaction of HPV16 E7 with GSN, since HPV16 E7 deletion mutants unable to bind to GSN were also unable to modify microfilament assembly dynamics and, therefore, cell movements and invasiveness. Altogether, these data profile the importance of the physical interaction between HPV16 E7 and GSN in the acquisition of the metastatic phenotype by CC cells, underscoring the role of HPV16 intracellular load as a risk factor in cancer.