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

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.

Treatment of Idiopathic Pulmonary Fibrosis by Inhaled Silybin Dry Powder Prepared via the Nanosuspension Spray Drying Technology

“…The effect of silybin on MMPs may also be produced via the TGF-β pathway. 22 These need to be studied in depth in subsequent experiments.…”

Conformation-Specific Inhibitory Anti-MMP-7 Monoclonal Antibody Sensitizes Pancreatic Ductal Adenocarcinoma Cells to Chemotherapeutic Cell Kill

“…High MMP-7 level is an independent predictor of docetaxel resistance and poor cancer survival in patients with castration-resistant prostate cancer (CRPC) [ 59 ]. Enhanced drug efflux activity was found to be correlated with induced expression and activity of MMP-7 in a HSP-90 dependent manner [ 60 ]. Activation of MMP-7 by DKK1 and Wnt/β-catenin pathway is known to induce T-DM1 or ado-trastuzumab resistance, and lead to poor prognosis in gastric adenocarcinoma [ 61 ].…”

Emerging concepts in cancer therapy: Mechanisms of resistance

“…Establishing a vincristine-cisplatin resistant human carcinoma cells (KB), A. Sridhar and colleagues showed that a cross talk between matrix metalloprotease 7 (MMP 7) and heat shock protein 90 (HSP90) could facilitate tumor progression and metastatic potential besides leading to acquired drug resistance. 6 They also demonstrated that enhanced homing in MMP7 overexpressing tumor cells could be inhibited using the HSP90 inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG). 6 Since MMP7 inhibitors are already undergoing clinical trials, while HSP90 inhibitors are awaiting approval, their findings provide a novel approach for overcoming drug resistance by targeting simultaneously MMP7 and HSP90.…”

“…Establishing a vincristine–cisplatin resistant human carcinoma cells (KB), A. Sridhar and colleagues showed that a cross talk between matrix metalloprotease 7 (MMP 7) and heat shock protein 90 (HSP90) could facilitate tumor progression and metastatic potential besides leading to acquired drug resistance. 6 They also demonstrated that enhanced homing in MMP7 overexpressing tumor cells could be inhibited using the HSP90 inhibitor 17‐allylamino‐17‐demethoxy‐geldanamycin (17‐AAG). 6 Since MMP7 inhibitors are already undergoing clinical trials, while HSP90 inhibitors are awaiting approval, their findings provide a novel approach for overcoming drug resistance by targeting simultaneously MMP7 and HSP90.…”

“… 6 They also demonstrated that enhanced homing in MMP7 overexpressing tumor cells could be inhibited using the HSP90 inhibitor 17‐allylamino‐17‐demethoxy‐geldanamycin (17‐AAG). 6 Since MMP7 inhibitors are already undergoing clinical trials, while HSP90 inhibitors are awaiting approval, their findings provide a novel approach for overcoming drug resistance by targeting simultaneously MMP7 and HSP90.…”