The matrix metalloproteinase 7 (MMP7) links Hsp90 chaperone with acquired drug resistance and tumor metastasis

Abstract

Abstract Background Cancer emergence is associated with a series of cellular transformations that include acquired drug resistance followed by tumor metastasis. Matrix metalloproteinases (MMPs) and Hsp90 chaperone are implicated in tumor progression, however, they are not studied in the context of drug resistance. Aims In the present study, we aimed at understanding the cross‐talk between acquired drug resistance and tumor progression, linking MMP7 and Hsp90. Methods and results We have developed an in vitro model system for acquired drug resistance and studied the correlation between MMP7 and Hsp90. We demonstrate that enhanced drug efflux activity correlates with the induced expression and activity of MMP7, and enhanced metastatic potential of cells, however, in Hsp90‐dependent manner. The MMP7 overexpression alone could enhance the drug efflux activity marginally, and metastasis significantly. However, challenging these cells with 17AAG has significantly increased the drug efflux activity and, in contrast, decreased the metastatic potential. Evaluating our in vitro findings in mice xenografts revealed that MMP7 overexpression facilitates altered homing properties. However, these cells, in response to 17AAG treatment, exhibited increased localized tumor growth but decreased tumor metastasis. Conclusion We demonstrated a cross‐talk between Hsp90 and MMP7 in regulating the acquired drug resistance and tumor progression. Our findings provide novel insights on targeting drug resistant‐tumors.

Keywords

• Cancer
• drug resistance
• Hsp90
• metastasis
• MMP7