Leticia Batista Azevedo Rangel

Epithelial ovarian cancer (EOC) is an alarming malignancy with frequent relapse and resistance to chemotherapy. Understanding the mechanism related to thes

Introduction: Chemoresistance and disease relapses in epithelial ovarian cancer (EOC) highlight the need for novel therapeutic strategies. Here, we investigated phosphodiesterase 7A (PDE7A) as a potential target in ovarian cancer treatment.Methods: Gene expression was performed by RNA sequencing data comparing high-grade serous ovarian carcinoma (HGSOC) and fallopian tube samples. The PDE7 inhibitor BRL 50481, alone or combined with paclitaxel (PTX), was tested in drug-sensitive A2780 and multi-resistant OVCAR3 cells by Diphenyltetrazolium bromide (MTT) assay. To validate data from the high throughput RNA-sequencing assays, RT-qPCR and Immunoblotting were performed. Cytokine expression was analyzed by RT-qPCR and the quantification was obtained by ELISA. Scanning and Transmission Electron Microscopy were also carried out.Results and discussion: MTT assays revealed that while BRL 50481 reduced metabolic cellular viability (MCV) in A2780 (IC50 = 200 μM), its combination with PTX decreased MCV in both lines, reducing PTX IC50 by 103- and 625-fold in A2780 and OVCAR3, respectively. PDE7 inhibition suppressed the PI3K/AKT/mTOR pathway, upregulated the pro-apoptotic protein Bcl-2 Associated X-protein (BAX) in A2780, and increased IL-6 expression in OVCAR3. Pretreatment with BRL 50481 followed by PTX downregulated vimentin and octamer-binding transcription factor (OCT4), while inducing morphological changes and mitochondrial cristae alterations. Inhibiting PDE7 can enhance the paclitaxel-induced apoptosis by promoting mitochondrial dysfunction and suppressing survival pathways, thereby improving ovarian cancer treatment efficacy. The results need to be validated in additional in vivo models.

Cellular senescence and polyploid giant cancer cells (PGCCs) constitute distinct, yet interconnected, stress adaptation cellular programs that critically shape breast cancer (BC) progression and therapeutic response. Senescence arises via replicative, oncogene-induced, or therapy-induced mechanisms, and it is characterized by stable cell-cycle arrest and secretion of a senescence-associated secretory phenotype (SASP). Senescence can transiently suppress tumor growth; however, persistent senescence may ultimately facilitate immune evasion, cell survival, and chemoresistance. In turn PGCCs development comprises cytokinesis failure, endoreplication, or mitotic slippage and are notable for their enlarged morphology, genomic plasticity, and the ability to generate therapy-resistant progeny through atypical divisions. Both cell states often co-occur following genotoxic stress, as senescent cells can become polyploid and PGCCs may display senescence-associated features, complicating their distinction. While resistance mediated by therapy-induced senescence (TIS) is mainly driven by SASP signaling and reversible arrest, PGCC-driven resistance is associated with genetic diversification, acquisition of stemness, and long-term persistence. Therapeutic strategies include senolytics and senomorphics, as well as emerging PGCC-targeted approaches. By integrating morphological, molecular, and ploidy-based approaches to distinguish these phenotypes, this review aims to clarify their overlapping and divergent roles in BC chemoresistance and to highlight opportunities for more effective therapeutic interventions.

Ovarian cancer is the second most common malignant neoplasm of gynecological origin and the leading cause of death from cancer in the female reproductive system worldwide. This scenario is largely due to late diagnoses, often in advanced stages, and the development of chemoresistance by cancer cells. These challenges highlight the need for alternative treatments, with immunotherapy being a promising option. Cancer immunotherapy involves triggering an anti-tumor immune response and developing immunological memory to eliminate malignant cells, prevent recurrence, and inhibit metastasis. Some ongoing research investigate potentially immunological advancements in the field of cancer vaccines, immune checkpoint blockade, CAR-T cell, and other strategies.

This study aimed to compare the subgingival microbiota of subjects with and without breast cancer (BC). Patients with BC (Group 1; n= 50) and without BC (Group 2; n=50) with periodontitis (A) and without periodontitis (B). The study was conducted in two phases (P1 and P2). One biofilm sample was collected from each subject and analyzed by DNA-DNA Hybridization (Checkerboard DNA-DNA). The relative abundance of the subgingival microbiota differed between the Case and Control groups. However, some species were higher in patients in the Case than in Control subjects and differed between the groups in both phases. Composition of the subgingival microbial community according to the Socransky complex was related to periodontal disease, followed by clinical attachment of level (CAL ≥4mm), age, and tooth loss, which were found to be abundant in Cases when compared with controls. Patients with Tumor Grade II and III had a higher prevalence of tooth loss and CAL≥4mm. It was concluded that in individuals with BC, the sub-gingival microbiota exhibited atypical changes, but they developed periodontal disease.

Background: Breast cancer (BC) is the second most frequent type of cancer in the world and most common among women, configuring a major challenge to global health. BC is a complex and heterogeneous disease that can be subdivided into distinct tumor types based on the expression of molecular markers predicting patient outcomes and response to therapy. A growing number of studies have tried to expand the known markers by investigating the association of altered lipid metabolism with BC immune escape, progression, and metastasis. In this review, we describe the metabolic peculiarities of each BC subtype, understanding how this influences its aggressiveness and identifying whether these intrinsic vulnerabilities of each subtype can play a role in therapeutic management and may affect immune system cells in the tumor microenvironment. Conclusion: The evidence suggests so far that when changes occur in lipid pathways, it can affect the availability of structural lipids for membrane synthesis, lipid synthesis, and degradation that contribute to energy homeostasis and cell signaling functions. These findings will guide the next steps on the path to understanding the mechanisms underlying how lipids alterations are related to disparities in chemotherapeutic response and immune escape in BC.

Journal of Cancer Metastasis and Treatment is an open access journal, focusing on basic and clinical studies related to cancer cell, cell biology, oncology, radiation therapy and radiology, obstetrics and gynecology, pediatrics, surgery, hematology, neuro-oncology, etc.

Background: Acquired treatment resistance is a significant problem in breast cancer management, and alterations in lipid metabolism have been proposed to contribute to the development of drug resistance as well as other aspects of tumor progression. The present study aimed to identify the role of cholesterol metabolism in MCF-7 and MDA-MB-231 breast cancer cell response to cisplatin (CDDP) treatment in the acute setting and in a model of CDDP resistance. Methods: MCF-7 (luminal A), MDA-MB-231 (triple-negative) and CDDP-resistant MDA-MB-231 (MDACR) cell lines were grown in the presence or absence of CDDP in combination with atorvastatin (ATV), lipid depletion or low-density lipoprotein loading and were analyzed by a variety of biochemical and radiometric techniques. Results: Co-administration of CDDP and ATV strongly reduced cell proliferation and viability to a greater extent than CDDP alone, especially in MDA-MB-231 cells. These findings were associated with reduced cholesteryl ester synthesis and storage in MDA-MB-231 cells. In MDACR cells, acetyl-CoA acetyltransferase 1 (ACAT-1) was upregulated compared to naïve MDA-MB-231 cells and ATV treatment restored CDDP sensitivity, suggesting that aberrant ACAT-1 expression and associated changes in cholesterol metabolism contribute to CDDP resistance in MDA-MB-231 cells. Conclusion: These findings indicate that the elevated susceptibility of MDA-MB-231 cells to co-administration of CDDP and ATV, is associated with an increased reliance on cholesteryl ester availability. Our data from these cell culture-based studies identifies altered cholesterol homeostasis as an adaptive response to CDDP treatment that contributes to aggressiveness and chemotherapy resistance.

Nucleus accumbens-associated protein 1 (NAC1) has multifaceted roles in cancer pathogenesis and progression, including the development of drug resistance, promotion of cytokinesis, and maintenance of "stem cell-like" phenotypes. NAC1 is a transcriptional co-regulator belonging to the bric-a-brac tramtrack broad (BTB) family of proteins, although it lacks the characteristic DNA binding motif of the BTB family. The formation of higher-order transcription complexes likely depends on its interaction with other DNA-binding co-factors. NAC1 interacts with BCL6 via its C-terminal BEN domain and forms a complex that binds the promoter region and activates transcription of the NAC1 target gene, FOXQ1. NAC1 and BCL6 were coordinately upregulated. Our analysis also identified a novel function of NAC1 in attenuating BCL6 auto-downregulation in ovarian cancer. Lastly, we found a significant overlap among NAC1- and BCL6-regulated genes in tumor cells, suggesting that NAC1 and BCL6 coordinately control transcription in cancer. The results of this study provide a novel mechanistic insight into the oncogenic roles of NAC1 and underline the importance of developing the NAC1/BCL6-targeted cancer therapy. Using the Cistrome database and Chromatin Immunoprecipitation (ChIP) analyses, we identified BCL6 as a potential NAC1- interacting molecule. Co-immunoprecipitation (Co-IP), luciferase reporter assay, immunohistochemistry and microarray analysis were performed to analyze the interaction between NAC1 and BCL6 and the mechanisms by which they regulate the downstream genes including FOXQ1.