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Published on: March 13, 2013
ADAM10 is the constitutive functional sheddase of CD44 in human melanoma cells
Ulf Anderegg1, Thea Eichenberg, Tanja Parthaune
1Department of Dermatology, Venerology and Allergology, Leipzig University Medical Center, Leipzig, Germany. Ulf.Anderegg@medizin.uni-leipzig.de
Insights
ADAM10 protease sheds CD44 (cell surface receptor) in melanoma. Blocking ADAM10 reduces CD44 shedding and melanoma cell proliferation, offering a potential therapeutic strategy.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- CD44 proteins are cell surface receptors for hyaluronic acid (HA), influencing cell behavior.
- Soluble CD44, generated by shedding, can inhibit HA's pro-proliferative effects on melanoma cells.
- Understanding CD44 shedding is key to developing strategies against tumor cell proliferation.
Purpose of the Study:
- To investigate the specific proteases involved in CD44 shedding in melanoma.
- To determine the role of ADAM10, ADAM17, and MMP14 in CD44 shedding and its impact on melanoma cell proliferation.
Main Methods:
- Immunohistochemistry to assess protease expression in melanoma tissues.
- siRNA-mediated knockdown of ADAM10, ADAM17, and MMP14 in melanoma cell lines.
- Confocal microscopy to visualize CD44 and ADAM10 colocalization.
- Assessing CD44 shedding and cell proliferation rates after protease inhibition.
Main Results:
- ADAM10 and ADAM17 were significantly expressed on melanoma cells; MMP14 was not.
- Blocking ADAM10, but not ADAM17 or MMP14, significantly decreased CD44 shedding.
- ADAM10 and CD44 were found to colocalize on the cell surface.
- Inhibition of ADAM10 led to decreased CD44 shedding and promoted melanoma cell proliferation.
Conclusions:
- ADAM10 is the primary protease responsible for constitutive CD44 shedding in melanoma cells.
- Targeting ADAM10 activity presents a potential therapeutic approach to reduce melanoma cell proliferation.
Abstract:
CD44 proteins are cell surface receptors for hyaluronic acid (HA), a component of the extracellular matrix that has multiple effects on cell behavior. CD44 can be shed from the cell surface by proteolytic cleavage. The resulting soluble form can interfere with the interaction between HA and membrane-bound CD44. Soluble CD44 can abolish the cell proliferation-promoting effect of HA on melanoma cell lines, suggesting that a better understanding of the shedding process might identify ways of blocking tumor cell proliferation. ADAM10, ADAM17, and MMP14 have previously been implicated in the shedding of CD44 from various tumor cells. Using immunohistochemistry we demonstrate that ADAM10 and ADAM17 but not MMP14 are significantly expressed on melanoma cells in histological sections. In human melanoma cell lines expression of these proteases could be blocked by transfection with appropriate siRNAs. However, only blocking of ADAM10 expression led to decreased shedding of CD44. In parallel, cell proliferation was promoted. Confocal microscopy demonstrated that ADAM10 and CD44 colocalize on the cell surface. We conclude that ADAM10 is the predominant protease involved in the constitutive shedding of endogenous CD44 from melanoma cells, and that enhancement of ADAM10 activity could be an approach to decrease the proliferation of melanoma cells.
