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Published on: February 1, 2020
Targeting Hedgehog Pathway and DNA Methyltransferases in Uterine Leiomyosarcoma Cells
Natalia Garcia1,2, Ayman Al-Hendy1,3, Edmund C Baracat2
1Department of Surgery, University of Illinois at Chicago, Chicago, IL 60607, USA.
Abstract:
Uterine leiomyosarcoma (LMS) is an aggressive tumor that presents poor prognosis, high rates of recurrence and metastasis. Because of its rarity, there is no information available concerning LMS molecular mechanisms of origin and development. Here, we assessed the expression profile of Hedgehog (HH) signaling pathway markers and the effects of their pharmacological inhibition on uterine smooth muscle (UTSM), leiomyoma and LMS cells. Additionally, we also evaluated the effects of DNMTs inhibition on LMS cells behavior. Cell proliferation, migration and apoptosis rates were evaluated by MTT, Scratch and Annexin V assays, respectively. RNA expression and protein levels were assessed by qRT-PCR and Western blot. We found that SMO and GLIs (1, 2 and 3) expression was upregulated in LMS cells, with increased nuclear levels of GLI proteins. Treatment with LDE225 (SMOi) and Gant61 (GLIi) resulted in a significant reduction in Glis protein levels in LMS (p < 0.05). Additionally, the expression of DNMT (1, 3a, and 3b), as well as GLI1 nuclear expression, was significantly decreased after treatment with HH inhibitor in LMS cells. Our results showed that blocking of SMO, GLI and DNMTs is able to inhibit LMS proliferation, migration and invasion. Importantly, the combination of those treatments exhibited a potentiated effect on LMS malignant features due to HH pathway deactivation.
Insights
Hedgehog pathway inhibition significantly reduces uterine leiomyosarcoma (LMS) cell proliferation and migration. Blocking SMO, GLI, and DNMTs effectively inhibits LMS progression, offering potential therapeutic strategies for this aggressive cancer.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Uterine leiomyosarcoma (LMS) is an aggressive gynecologic cancer with poor prognosis.
- The molecular mechanisms driving LMS development and progression remain poorly understood.
- The Hedgehog (HH) signaling pathway is implicated in various cancers but its role in LMS is unclear.
Purpose of the Study:
- To investigate the expression of Hedgehog (HH) signaling pathway markers in LMS.
- To evaluate the effects of pharmacological inhibition of HH pathway components (SMO and GLI) and DNA methyltransferases (DNMTs) on LMS cell behavior.
- To explore the potential of combined therapeutic strategies targeting HH and DNMTs in LMS.
Main Methods:
- Assessed expression of HH pathway markers (SMO, GLI1-3) and DNMTs (1, 3a, 3b) in LMS cells using qRT-PCR and Western blot.
- Evaluated cell proliferation, migration, and apoptosis using MTT, Scratch, and Annexin V assays.
- Treated LMS cells with SMO inhibitor (LDE225) and GLI inhibitor (Gant61), and DNMTs inhibitors.
Main Results:
- SMO and GLI (1-3) expression and nuclear GLI protein levels were upregulated in LMS cells.
- Pharmacological inhibition of SMO and GLI significantly reduced GLI protein levels in LMS cells.
- Inhibition of HH pathway and DNMTs decreased LMS cell proliferation, migration, and invasion.
- Combined inhibition demonstrated a potentiated anti-cancer effect by deactivating the HH pathway.
Conclusions:
- The Hedgehog signaling pathway is active in uterine leiomyosarcoma and contributes to its malignant phenotype.
- Pharmacological targeting of SMO, GLI, and DNMTs represents a promising therapeutic strategy for LMS.
- Combined inhibition of these targets shows enhanced efficacy in controlling LMS progression, warranting further investigation.
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