ARID1A Regulates Progesterone Receptor Expression in Early Endometrial Endometrioid Carcinoma Pathogenesis.

Loss of progesterone receptor (PR) expression is an established risk factor for unresponsiveness to progesterone therapy in patients with endometrial atypical hyperplasia and endometrioid carcinoma. ARID1A is one of the most commonly mutated genes in endometrioid carcinomas, and the loss of its expression is associated with tumor progression. In this study, we investigated the roles of ARID1A deficiency in PR expression in human and murine endometrial epithelial neoplasia.

Development of small molecule inhibitors targeting PBX1 transcription signaling as a novel cancer therapeutic strategy.

PBX1 is a transcription factor involved in diverse cellular functions including organ development, stem cell renewal, and tumorigenesis. is localized at chr1q23.3, a frequently amplified chromosomal region, and it is overexpressed in many human malignancies.

Inhibition of the MYC-Regulated Glutaminase Metabolic Axis Is an Effective Synthetic Lethal Approach for Treating Chemoresistant Ovarian Cancers.

Amplification and overexpression of the oncogene in tumor cells, including ovarian cancer cells, correlates with poor responses to chemotherapy. As MYC is not directly targetable, we have analyzed molecular pathways downstream of MYC to identify potential therapeutic targets. Here we report that ovarian cancer cells overexpressing glutaminase (GLS), a target of MYC and a key enzyme in glutaminolysis, are intrinsically resistant to platinum-based chemotherapy and are enriched with intracellular antioxidant glutathione.

Inactivation of Arid1a in the endometrium is associated with endometrioid tumorigenesis through transcriptional reprogramming.

Somatic inactivating mutations of ARID1A, a SWI/SNF chromatin remodeling gene, are prevalent in human endometrium-related malignancies. To elucidate the mechanisms underlying how ARID1A deleterious mutation contributes to tumorigenesis, we establish genetically engineered murine models with Arid1a and/or Pten conditional deletion in the endometrium. Transcriptomic analyses on endometrial cancers and precursors derived from these mouse models show a close resemblance to human uterine endometrioid carcinomas.

Acireductone dioxygenase 1 (ADI1) is regulated by cellular iron by a mechanism involving the iron chaperone, PCBP1, with PCBP2 acting as a potential co-chaperone.

The iron-containing protein, acireductone dioxygenase 1 (ADI1), is a dioxygenase important for polyamine synthesis and proliferation. Using differential proteomics, the studies herein demonstrated that ADI1 was significantly down-regulated by cellular iron depletion. This is important, since ADI1 contains a non-heme, iron-binding site critical for its activity.

Relationship between ovarian cancer stem cells, epithelial mesenchymal transition and tumour recurrence.

Investigating the biological processes that occur to enable recurrence and the development of chemoresistance in ovarian cancer is critical to the research and development of improved treatment options for patients. The lethality of ovarian cancer is largely attributed to the recurrence of disease with acquired chemoresistance. Cancer stem cells are likely to be critical in ovarian cancer progression, contributing to tumour malignancy, metastasis and recurrence by persisting in the body despite treatment with anti-cancer drugs.

Therapeutic Inducers of Apoptosis in Ovarian Cancer.

Ovarian cancers remain one of the most common causes of gynecologic cancer-related death in women worldwide. The standard treatment comprises platinum-based chemotherapy, and most tumors develop resistance to therapeutic drugs. One mechanism of developing drug resistance is alterations of molecules involved in apoptosis, ultimately assisting in the cells' capability to evade death.

Spleen tyrosine kinase activity regulates epidermal growth factor receptor signaling pathway in ovarian cancer.

Background: Spleen tyrosine kinase (SYK) is frequently upregulated in recurrent ovarian carcinomas, for which effective therapy is urgently needed. SYK phosphorylates several substrates, but their translational implications remain unclear. Here, we show that SYK interacts with EGFR and ERBB2, and directly enhances their phosphorylation.

TET1 reprograms the epithelial ovarian cancer epigenome and reveals casein kinase 2α as a therapeutic target.

Ten-eleven translocation methylcytosine dioxygenase-1, TET1, takes part in active DNA demethylation. However, our understanding of DNA demethylation in cancer biology and its clinical significance remain limited. This study showed that TET1 expression correlated with poor survival in advanced-stage epithelial ovarian carcinoma (EOC), and with cell migration, anchorage-independent growth, cancer stemness, and tumorigenicity.

Mechanisms underlying acquired platinum resistance in high grade serous ovarian cancer - a mini review.

Background: Advanced epithelial ovarian cancer is one of the hardest human malignancies to treat. Standard treatment involves cytoreductive surgery and platinum-based chemotherapy, however, median progression-free survival for patients diagnosed with advanced stage disease (FIGO stages III and IV) is approximately 18 months. There has been little improvement in overall survival over the past decade and less than half of women with advanced stage disease will be living 5 years after diagnosis.

Coupling of the polyamine and iron metabolism pathways in the regulation of proliferation: Mechanistic links to alterations in key polyamine biosynthetic and catabolic enzymes.

Many biological processes result from the coupling of metabolic pathways. Considering this, proliferation depends on adequate iron and polyamines, and although iron-depletion impairs proliferation, the metabolic link between iron and polyamine metabolism has never been thoroughly investigated. This is important to decipher, as many disease states demonstrate co-dysregulation of iron and polyamine metabolism.

Inhibition of ovarian tumor cell invasiveness by targeting SYK in the tyrosine kinase signaling pathway.

Cell motility and invasiveness are prerequisites for dissemination, and largely account for cancer mortality. We have identified an actionable kinase, spleen tyrosine kinase (SYK), which is keenly tightly associated with tumor progression in ovarian cancer. Here, we report that active recombinant SYK directly phosphorylates cortactin and cofilin, which are critically involved in assembly and dynamics of actin filament through phosphorylation signaling.

Drug repositioning of mevalonate pathway inhibitors as antitumor agents for ovarian cancer.

Drug repositioning is an alternative strategy redirecting existing drugs for new disease. We have previously reported an antitumor effect of statins, antidyslipidemic drugs, on ovarian cancer and . In this study, we investigated the antitumor effects of other mevalonate pathway inhibitors and the mechanism of the antitumor effect from a metabolic perspective.

Mutation of NRAS is a rare genetic event in ovarian low-grade serous carcinoma.

Activating mutations involving the members of the RAS signaling pathway, including KRAS, NRAS, and BRAF, have been reported in ovarian low-grade serous carcinoma and its precursor lesion, serous borderline tumor (SBT). Whether additional genetic alterations in the RAS oncogene family accumulate during the progression of SBT to invasive low-grade serous carcinoma (LGSC) remains largely unknown. Although mutations of KRAS and BRAF occur at a very early stage of progression, even preceding the development of SBT, additional driving events, such as NRAS mutations, have been postulated to facilitate progression.

Increased proliferation in atypical hyperplasia/endometrioid intraepithelial neoplasia of the endometrium with concurrent inactivation of ARID1A and PTEN tumour suppressors.

Uterine endometrioid carcinoma is the most common neoplastic disease in the female genital tract and develops from a common precursor lesion, atypical hyperplasia/endometrioid intraepithelial neoplasia (AH/EIN). Although the genomic landscape of endometrioid carcinoma has been recently revealed, the molecular alterations that contribute to tumour progression from AH/EIN to carcinoma remain to be elucidated. In this study, we used immunohistochemistry to determine if loss of expression of two of the most commonly mutated tumour suppressors in endometrioid carcinoma, PTEN and ARID1A, was associated with increased proliferation in AH/EIN.

Inactivating ARID1A Tumor Suppressor Enhances TERT Transcription and Maintains Telomere Length in Cancer Cells.

ARID1A is a tumor suppressor gene that belongs to the switch/sucrose non-fermentable chromatin remodeling gene family. It is mutated in many types of human cancer with the highest frequency in endometrium-related ovarian and uterine neoplasms including ovarian clear cell, ovarian endometrioid, and uterine endometrioid carcinomas. We have previously reported that mutations in the promoter of human telomerase reverse transcriptase (TERT) rarely co-occur with the loss of ARID1A protein expression, suggesting a potential role of ARID1A in telomere biology.

Roles of deletion of Arid1a, a tumor suppressor, in mouse ovarian tumorigenesis.

The chromatin remodeling gene, ARID1A, has been implied as a tumor suppressor, and its somatic inactivating mutations occur in a wide variety of human cancers, most frequently in ovarian and uterine endometrioid and ovarian clear cell carcinomas. Tumors with ARID1A mutations also frequently harbor PTEN or PIK3CA mutations, suggesting their collaboration in tumorigenesis. Here, we used a conditional knockout mouse model in which Arid1a and Pten were deleted either individually or in combination in the mouse ovarian surface epithelium.

Hepcidin bound to α2-macroglobulin reduces ferroportin-1 expression and enhances its activity at reducing serum iron levels.

Hepcidin regulates iron metabolism by down-regulating ferroportin-1 (Fpn1). We demonstrated that hepcidin is complexed to the blood transport protein, α2-macroglobulin (α2M) (Peslova, G., Petrak, J.

N-myc downstream regulated 1 (NDRG1) is regulated by eukaryotic initiation factor 3a (eIF3a) during cellular stress caused by iron depletion.

Iron is critical for cellular proliferation and its depletion leads to a suppression of both DNA synthesis and global translation. These observations suggest that iron depletion may trigger a cellular "stress response". A canonical response of cells to stress is the formation of stress granules, which are dynamic cytoplasmic aggregates containing stalled pre-initiation complexes that function as mRNA triage centers.

Identification of nonferritin mitochondrial iron deposits in a mouse model of Friedreich ataxia.

There is no effective treatment for the cardiomyopathy of the most common autosomal recessive ataxia, Friedreich ataxia (FA). This disease is due to decreased expression of the mitochondrial protein, frataxin, which leads to alterations in mitochondrial iron (Fe) metabolism. The identification of potentially toxic mitochondrial Fe deposits in FA suggests Fe plays a role in its pathogenesis.

Siderocalin/Lcn2/NGAL/24p3 does not drive apoptosis through gentisic acid mediated iron withdrawal in hematopoietic cell lines.

Siderocalin (also lipocalin 2, NGAL or 24p3) binds iron as complexes with specific siderophores, which are low molecular weight, ferric ion-specific chelators. In innate immunity, siderocalin slows the growth of infecting bacteria by sequestering bacterial ferric siderophores. Siderocalin also binds simple catechols, which can serve as siderophores in the damaged urinary tract.

Nitrogen monoxide (NO) storage and transport by dinitrosyl-dithiol-iron complexes: long-lived NO that is trafficked by interacting proteins.

Nitrogen monoxide (NO) markedly affects intracellular iron metabolism, and recent studies have shown that molecules traditionally involved in drug resistance, namely GST and MRP1 (multidrug resistance-associated protein 1), are critical molecular players in this process. This is mediated by interaction of these proteins with dinitrosyl-dithiol-iron complexes (Watts, R. N.

Nitric oxide storage and transport in cells are mediated by glutathione S-transferase P1-1 and multidrug resistance protein 1 via dinitrosyl iron complexes.

Nitrogen monoxide (NO) plays a role in the cytotoxic mechanisms of activated macrophages against tumor cells by inducing iron release. We showed that NO-mediated iron efflux from cells required glutathione (GSH) (Watts, R. N.