Simvastatin reduces plasma membrane caveolae and caveolin-1 in uterine leiomyomas.

AIMS: Uterine leiomyomas, or fibroids, are estrogen dependent benign tumor in women, however, they have limited treatment options. Simvastatin, a drug commonly used to treat high cholesterol. Recently we demonstrated that simvastatin alters estrogen signaling by reducing the expression and trafficking of the estrogen receptor-α (ER-α) in human uterine leiomyoma cells. Caveolae are invaginations of the plasma membrane where ER-α is known to localize and directly interacts with the caveolar protein caveolin-1 (CAV1). This study examines the effects of simvastatin on plasma membrane caveolae and the expression and palmitoylation of CAV1 in human leiomyomas which may influence ER-α signaling. MAIN METHODS: We performed in vitro experiments using primary and immortalized human uterine leiomyoma cells. The caveolae were quantified using transmission electron microscopy. Additionally, we examined the impact of simvastatin treatment (40 mg orally per day for 12 weeks) on human leiomyoma tissue obtained from a randomized controlled trial. The CAV1 protein and mRNA levels were determined using quantitative real-time polymerase chain reactions, western blotting, and immunofluorescence analyses. KEY FINDINGS: Simvastatin decreased the number of caveolae in primary leiomyoma cells and reduced CAV1 abundance in whole cells and remarkably the plasma protein fraction. It also decreased CAV1 palmitoylation, a post-translational modification associated with CAV1 activation. The effects of simvastatin on CAV1 were recapitulated in human leiomyoma tissue samples. SIGNIFICANCE: Our results identify caveolae and CAV1 as novel targets of simvastatin which may contribute to the recently described effects of simvastatin on ER-α signaling and plasma membrane trafficking.

Leptin induces leiomyoma cell proliferation and extracellular matrix deposition via JAK2/STAT3 and MAPK/ERK pathways.

OBJECTIVE: To investigate the molecular effects of leptin on uterine leiomyoma cells. DESIGN: Experimental study using in vitro culture of immortalized human leiomyoma (HuLM) cells. SETTING: Academic university center. PATIENT(S): Women with uterine fibroids who underwent a hysterectomy or myomectomy. INTERVENTION(S): Administration of human recombinant leptin to the media of cultured HuLM cells separately or in combination with pharmacologic Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) or mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) inhibitors. MAIN OUTCOME MEASURE(S): We examined HuLM tissues and cells for the expression of the leptin receptor, termed OB-R. Cellular proliferation was measured at 6, 24, and 48 hours using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide assay. Protein expression levels of proliferating cell nuclear antigen, collagen 1, phosphorylated STAT3/total STAT3, and phosphorylated ERK1/2 and total ERK1/2 were quantified using immunoblotting. Pharmacologic inhibitors were employed to further assess the role of the JAK2/STAT3 and MAPK/ERK pathways in the proliferative response. RESULT(S): The presence of OB-R was confirmed in clinical leiomyoma and myometrial tissue obtained from 3 separate human subjects using immunofluorescence staining, and the expression of OB-R in HuLM cells was identified using immunoblotting. There was no significant difference in the expression of the leptin receptor in the myometrium compared with that in the leiomyoma tissue. Leptin stimulated cell proliferation and extracellular matrix (ECM) deposition at 24 hours after treatment. Pretreatment with a JAK2/STAT3 inhibitor attenuated ECM deposition, and pretreatment with a MAPK/ERK inhibitor significantly decreased leptin's stimulatory effect on cell proliferation and ECM deposition. CONCLUSION(S): Leptin induces a proliferative response and ECM deposition in HuLM cells. These findings suggest that leptin, acting through the JAK2/STAT3 and MAPK/ERK pathways, is involved in the development of uterine leiomyomas, which may partly explain their increased incidence in obese women.

Predictors of Academic Neurosurgical Career Trajectory among International Medical Graduates Training Within the United States.

BACKGROUND: Within the literature, there has been limited research tracking the career trajectories of international medical graduates (IMGs) following residency training. OBJECTIVE: To compare the characteristics of IMG and US medical school graduate (USMG) neurosurgeons holding academic positions in the United States and also analyze factors that influence IMG career trajectories following US-based residency training. METHODS: We collected data on 243 IMGs and 2506 USMGs who graduated from Accreditation Council for Graduate Medical Education (ACGME)-accredited neurosurgery residency programs. We assessed for significant differences between cohorts, and a logistic regression model was used for the outcome of academic career trajectory. RESULTS: Among the 2749 neurosurgeons in our study, IMGs were more likely to pursue academic neurosurgery careers relative to USMGs (59.7% vs 51.1%; P = .011) and were also more likely to complete a research fellowship before beginning residency (odds ratio [OR] = 9.19; P < .0001). Among current US academic neurosurgeons, USMGs had significantly higher pre-residency h-indices relative to IMGs (1.23 vs 1.01; P < .0001) with no significant differences between cohorts when comparing h-indices during (USMG = 5.02, IMG = 4.80; P = .67) or after (USMG = 14.05, IMG = 13.90; P = .72) residency. Completion of a post-residency clinical fellowship was the only factor independently associated with an academic career trajectory among IMGs (OR = 1.73, P = .046). CONCLUSION: Our study suggests that while IMGs begin their US residency training with different research backgrounds and achievements relative to USMG counterparts, they attain similar levels of academic productivity following residency. Furthermore, IMGs are more likely to pursue academic careers relative to USMGs. Our work may be useful for better understanding IMG career trajectories following US-based neurosurgery residency training.