RESUMEN
CONTEXT: Proliferating cells reprogram their cellular glucose metabolism to meet the bioenergetic and biosynthetic demands and to maintain cellular redox homeostasis. Pyruvate kinase M (PKM) is a critical regulator of this metabolic reprogramming. However, whether estradiol-17ß (E2) reprograms cellular metabolism to support proliferation of human primary endometrial stromal cells (hESCs) and the molecular basis of this reprogramming are not well understood. OBJECTIVES: Our objectives were to study whether E2 induces reprogramming of glucose metabolism in hESCs and to investigate the potential roles of PKM2 in E2-induced metabolic reprogramming and proliferation of these cells. METHODS: The oxygen consumption rate and extracellular acidification rate were assessed by a Seahorse XF24 analyzer. PKM2 expression was assessed by real-time RT-PCR and immunoblotting. RESULTS: E2 induces a Warburg-like glucose metabolism in hESCs by inducing the expression of PKM. E2 also enhanced PKM splicing into the PKM2 isoform by upregulating the c-Myc-hnRNP axis. Furthermore, E2 induces PKM2 oxidation, phosphorylation, and nuclear translocation. In addition to its glycolytic function, PKM2 physically interacted with estrogen receptor-α (ERα) and functioned as an ERα coactivator. Small-molecule PKM2 activators ameliorated ERα transcriptional activity and abrogated the E2-induced hESC proliferation. CONCLUSIONS: We show for the first time that E2-induced hESC proliferation is associated with a shift in glucose metabolism toward aerobic glycolysis, and the molecular basis for this metabolic shift is linked to the effects of E2 on PKM2. In addition, PKM2 acts as a transcriptional coactivator for ERα and small-molecule PKM2 activators inhibit ERα transcriptional activity and reduce E2-induced cell proliferation.
Asunto(s)
Estradiol/fisiología , Receptor alfa de Estrógeno/metabolismo , Piruvato Quinasa/metabolismo , Células del Estroma/metabolismo , Empalme Alternativo/efectos de los fármacos , Empalme Alternativo/fisiología , Proliferación Celular/efectos de los fármacos , Proliferación Celular/fisiología , Reprogramación Celular/efectos de los fármacos , Reprogramación Celular/fisiología , Endometrio/citología , Estradiol/farmacología , Receptor alfa de Estrógeno/genética , Estrógenos/farmacología , Estrógenos/fisiología , Femenino , Glucosa/metabolismo , Humanos , Ácido Láctico/metabolismo , Mitógenos/metabolismo , Consumo de Oxígeno/efectos de los fármacos , Consumo de Oxígeno/fisiología , Cultivo Primario de Células , Piruvato Quinasa/genética , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiología , Células del Estroma/citología , Células del Estroma/efectos de los fármacos , Transcripción Genética/efectos de los fármacos , Transcripción Genética/fisiologíaRESUMEN
OBJECTIVE: To describe the rate of port-site metastasis in patients who underwent robotic surgery for suspected gynecological malignancy. METHODS: Using a prospective database, we identified all patients who underwent robotic surgery performed by the Gynecologic Oncology service at 1 institution between December 2006 and March 2010. Records of patients with confirmed malignancy were reviewed for clinicopathological data and information about port-site metastasis. RESULTS: One hundred eighty-one patients met the inclusion criteria. The median age was 55.4 years (range, 19-82 years), and the median body mass index was 29.6 kg/m² (range, 17.9-70.7 kg/m²). Port-site metastases were detected in 2 patients (1.1%) at 3 weeks (patient 1) and 11 months (patient 2) after surgery. Patient 1 underwent surgery for an adnexal mass, and pathological examination revealed gallbladder adenocarcinoma metastatic to the ovary. She had a recurrence in the right lateral abdominal wall robotic trocar site with concurrent metastases in the gallbladder fossa and liver. Patient 2 was diagnosed with adenocarcinoma of unclear (cervical vs endometrial) origin. Imaging showed metastases in pelvic and para-aortic lymph nodes. She underwent laparoscopy and was found intraoperatively to have gross disease on the right ovary. The patient underwent right salpingo-oophorectomy and chemoradiation. She had residual disease in the cervix and subsequently underwent robotic hysterectomy and left salpingo-oophorectomy. Pathological examination revealed endometrial cancer. She had a recurrence at the transumbilical trocar site concurrent with retroperitoneal lymphadenopathy and carcinomatosis. There were no cases of isolated port-site metastasis. CONCLUSIONS: The rate of port-site metastasis after robotic surgery in women with gynecological cancer is low and similar to the rate for laparoscopic procedures.