RESUMO
Metformin (MET) is increasingly implicated in reducing the incidence of multiple cancer types in patients with diabetes. However, similar effects of MET in non-diabetic women with endometrial cancer (EC) remain unknown. In a pilot study, obese non-diabetic women diagnosed with type 1, grade 1/2 EC, and consenting to participate were randomly assigned to receive MET or no MET (control (CON)) during the pre-surgical window between diagnosis and hysterectomy. Endometrial tumors obtained at surgery (MET, n = 4; CON, n = 4) were analyzed for proliferation (Ki67), apoptosis (TUNEL), and nuclear expression of ERα, PGR, PTEN, and KLF9 proteins in tumor glandular epithelial (GE) and stromal (ST) cells. The percentages of immunopositive cells for PGR and for KLF9 in GE and for PTEN in ST were higher while those for ERα in GE but not ST were lower, in tumors of MET vs. CON patients. The numbers of Ki67- and TUNEL-positive cells in tumor GE and ST did not differ between groups. In human Ishikawa endometrial cancer cells, MET treatment (60 µM) decreased cell numbers and elicited distinct temporal changes in ESR1, KLF9, PGR, PGR-B, KLF4, DKK1, and other tumor biomarker mRNA levels. In the context of reduced KLF9 expression (by siRNA targeting), MET rapidly amplified PGR, PGR-B, and KLF4 transcript levels. Our findings suggest that MET acts directly in EC cells to modify steroid receptor expression and signaling network and may constitute a preventative strategy against EC in high-risk non-diabetic women.
Assuntos
Proliferação de Células/efeitos dos fármacos , Neoplasias do Endométrio/metabolismo , Hipoglicemiantes/farmacologia , Metformina/farmacologia , Apoptose/efeitos dos fármacos , Biomarcadores Tumorais , Neoplasias do Endométrio/patologia , Neoplasias do Endométrio/cirurgia , Endométrio , Receptor alfa de Estrogênio/metabolismo , Feminino , Humanos , Fator 4 Semelhante a Kruppel , Fatores de Transcrição Kruppel-Like/metabolismo , Pessoa de Meia-Idade , PTEN Fosfo-Hidrolase/metabolismo , Projetos Piloto , Período Pré-Operatório , Receptores de Progesterona/metabolismoRESUMO
Type 1 diabetes mellitus and endometriosis separately affect millions of women worldwide. Reproductive-age women diagnosed with type 1 diabetes may also suffer from endometriosis, but the asymptomatic pre-clinical period of highly variable duration for each condition can lead to challenges in the timely recognition of co-morbid disease onset and misdiagnosis. While knowledge of the pathogenesis of each condition has grown substantially, co-morbid endometriosis and type 1 diabetes has not been widely considered and much less addressed. This review discusses the molecular rationale for the likelihood of their co-existence, and prospects for improvements in therapeutic strategies and reduced complications, if this paradigm is included as a significant variable in disease management.
RESUMO
Cytosolic Malic Enzyme (ME1) provides reduced NADP for anabolism and maintenance of redox status. To examine the role of ME1 in tumor genesis of the gastrointestinal tract, we crossed mice having augmented intestinal epithelial expression of ME1 (ME1-Tg mice) with ApcMin/+ mice to obtain male ApcMin/+/ME1-Tg mice. ME1 protein levels were significantly greater within gut epithelium and adenomas of male ApcMin/+/ME1-Tg than ApcMin/+ mice. Male ApcMin/+/ME1-Tg mice had larger and greater numbers of adenomas in the small intestine (jejunum and ileum) than male ApcMin/+ mice. Male ApcMin/+/ME1-Tg mice exhibited greater small intestine crypt depth and villus length in non-adenoma regions, correspondent with increased KLF9 protein abundance in crypts and lamina propria. Small intestines of male ApcMin/+/ME1-Tg mice also had enhanced levels of Sp5 mRNA, suggesting Wnt/ß-catenin pathway activation. A small molecule inhibitor of ME1 suppressed growth of human CRC cells in vitro, but had little effect on normal rat intestinal epithelial cells. Targeting of ME1 may add to the armentarium of therapies for cancers of the gastrointestinal tract.
Assuntos
Proteína da Polipose Adenomatosa do Colo/genética , Carcinogênese/genética , Neoplasias do Colo/genética , Trato Gastrointestinal/metabolismo , Malato Desidrogenase/genética , Animais , Proliferação de Células/genética , Neoplasias do Colo/patologia , Proteínas de Ligação a DNA/genética , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Trato Gastrointestinal/patologia , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Mucosa Intestinal , Malato Desidrogenase/antagonistas & inibidores , Camundongos , Oncogenes , Ratos , Fatores de Transcrição/genéticaRESUMO
CONTEXT: Progesterone (P) resistance is a hallmark of endometriosis, but the underlying mechanism(s) for loss of P sensitivity leading to lesion establishment remains poorly understood. OBJECTIVE: To evaluate the association between Notch-1 signaling activation and P resistance in the progression of endometriosis. DESIGN: Case control study; archived formalin-fixed, paraffin-embedded tissues. SETTING: University hospitals (United States, Taiwan). PATIENTS: Women with endometriosis; human endometrial stromal cell line (HESC). INTERVENTION: Eutopic endometria (EU) and ectopic lesions (ECs) were collected from surgically diagnosed patients. Archived tissue sections of EU and ECs were identified. HESCs were treated with N-[N-(3,5-difluorophenacetyl)-l-alanyl]-S-phenylglycine t-butyl ester (DAPT) and valproic acid (VPA) to, respectively, suppress and induce Notch-1 activation. OUTCOME MEASURES: Tissues were analyzed for Notch Intra-Cellular Domain 1 (NICD1) and progesterone receptor (PGR) protein expression by immunohistochemistry and for transcript levels of NICD1 target genes HES1, PGR, and PGR-B by quantitative reverse transcription polymerase chain reaction. DAPT- or VPA-treated HESCs with and without P cotreatment were evaluated for cell numbers and for PGR, HES1, and PGR target gene DKK1 transcript levels. RESULTS: Nuclear-localized stromal NICD1 protein levels were inversely associated with those of total PGR in EU and ECs. Stromal ECs displayed higher HES1 and lower total PGR and PGR-B transcript levels than EU. In HESCs, DAPT reduction of NICD1 decreased cell numbers and increased PGR transcript and nuclear PGR protein levels and, with P cotreatment, maintained P sensitivity. Conversely, VPA induction of NICD1 decreased PGR transcript levels and, with P cotreatment, abrogated P-induced DKK1 and maintained HES1 transcript levels. CONCLUSIONS: Aberrant Notch-1 activation is associated with decreased PGR that contributes to P resistance in endometriosis.