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An Impermeant Ganetespib Analog Inhibits Extracellular Hsp90-Mediated Cancer Cell Migration that Involves Lysyl
Jessica McCready1, Daniel S Wong2, Joseph A Burlison3
1Department of Natural Sciences, Assumption College, Worcester, MA 01609, USA. j.mccready@assumption.edu.
Cancers
|May 3, 2014
Summary
Extracellular heat shock protein 90 (eHsp90) drives cancer cell migration. New research identifies Lysyl oxidase 2-like protein (LOXL2) as a key eHsp90 client, suggesting eHsp90 and LOXL2 as targets for anti-metastatic drugs.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Extracellular heat shock protein 90 (eHsp90) promotes cancer cell migration and invasion by activating extracellular client proteins.
- Targeting eHsp90 with impermeant inhibitors offers a strategy for anti-metastatic drugs, sparing vital intracellular Hsp90 functions.
- Identifying novel eHsp90 clients is crucial for validating eHsp90 as a therapeutic target to impede cancer spread.
Purpose of the Study:
- To identify novel extracellular proteins associated with eHsp90 in breast cancer cells.
- To investigate the role of Lysyl oxidase 2-like protein (LOXL2) and Galectin 3 binding protein (G3BP) as potential eHsp90 clients.
- To evaluate the efficacy of a novel impermeant Hsp90 inhibitor, STA-12-7191, in blocking eHsp90-mediated cancer cell migration.
Main Methods:
- Mass spectrometry was employed to identify proteins interacting with eHsp90 in conditioned media from MDA-MB231 breast cancer cells.
- Immunoprecipitation assays were used to confirm the binding of LOXL2 to eHsp90.
- A novel impermeant Hsp90 inhibitor, STA-12-7191, was synthesized and tested for its effects on cell toxicity and migration, and its impact on LOXL2 and G3BP function was assessed in wound healing assays.
Main Results:
- Mass spectrometry identified G3BP and LOXL2 as proteins associated with eHsp90.
- LOXL2 was confirmed to bind to eHsp90.
- STA-12-7191 demonstrated reduced cellular toxicity and dose-dependent inhibition of cancer cell migration. LOXL2 enhanced wound healing, counteracting STA-12-7191's inhibitory effect, while G3BP showed no significant impact.
Conclusions:
- LOXL2 plays a role in eHsp90-stimulated cancer cell migration.
- The novel impermeant Hsp90 inhibitor STA-12-7191 shows potential for inhibiting eHsp90 activity.
- These findings support targeting eHsp90 and LOXL2 as a strategy to limit cancer invasion and metastasis.
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