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Sphingosine kinase transmits estrogen signaling in human breast cancer cells
Olga A Sukocheva1, Lijun Wang, Nathaniel Albanese
1Signal Transduction Laboratory, Division of Human Immunology, Hanson Institute, Institute of Medical and Veterinary Science and University of Adelaide, Adelaide, South Australia 5000, Australia.
Abstract:
Current understanding of cytoplasmic signaling pathways that mediate estrogen action in human breast cancer is incomplete. Here we report that treatment with 17beta-estradiol (E2) activates a novel signaling pathway via activation of sphingosine kinase (SphK) in MCF-7 breast cancer cells. We found that E2 has dual actions to stimulate SphK activity, i.e. a rapid and transient activation mediated by putative membrane G protein-coupled estrogen receptors (ER) and a delayed but prolonged activation relying on the transcriptional activity of ER. The E2-induced SphK activity consequently activates downstream signal cascades including intracellular Ca2+ mobilization and Erk1/2 activation. Enforced expression of human SphK type 1 gene in MCF-7 cells resulted in increases in SphK activity and cell growth. Moreover, the E2-dependent mitogenesis were highly promoted by SphK overexpression as determined by colony growth in soft agar and solid focus formation. In contrast, expression of SphKG82D, a dominant-negative mutant SphK, profoundly inhibited the E2-mediated Ca2+ mobilization, Erk1/2 activity and neoplastic cell growth. Thus, our data suggest that SphK activation is an important cytoplasmic signaling to transduce estrogen-dependent mitogenic and carcinogenic action in human breast cancer cells.
Insights
17beta-estradiol (E2) activates sphingosine kinase (SphK) in breast cancer cells. This SphK activation promotes cell growth and is crucial for estrogen-driven cancer progression.
Area of Science:
- Cell Biology
- Molecular Biology
- Biochemistry
Background:
- Estrogen signaling is critical in human breast cancer, but cytoplasmic pathways are not fully understood.
- Estrogen receptors (ER) mediate cellular responses, influencing proliferation and carcinogenesis.
Purpose of the Study:
- To investigate the role of sphingosine kinase (SphK) in estrogen-mediated signaling pathways in human breast cancer cells.
- To elucidate the mechanism by which 17beta-estradiol (E2) activates SphK and its downstream effects.
Main Methods:
- MCF-7 breast cancer cells were treated with 17beta-estradiol (E2).
- Sphingosine kinase (SphK) activity was measured.
- Downstream signaling cascades (Ca2+ mobilization, Erk1/2 activation) were analyzed.
- SphK gene expression and mutant SphK were used to assess functional roles.
Main Results:
- E2 rapidly and transiently activated SphK via membrane ER, and delayed, prolonged activation via transcriptional ER.
- E2-induced SphK activity led to increased intracellular Ca2+ mobilization and Erk1/2 activation.
- SphK overexpression enhanced E2-dependent cell growth, colony formation, and focus formation.
- A dominant-negative SphK mutant inhibited E2-mediated signaling and cell growth.
Conclusions:
- SphK activation is a key cytoplasmic signaling pathway for estrogen action in breast cancer.
- SphK mediates estrogen-dependent mitogenesis and carcinogenic effects.
- Targeting SphK may offer a therapeutic strategy for estrogen-driven breast cancers.
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