Cervical cancer is a common malignancy worldwide. Recent studies have shown that HIV-protease inhibitors (HIV-PIs), widely used in highly active antiretroviral therapy (HAART), led to a reduced incidence and/or regression of HIV-associated tumors. Although HIV suppression and restoration of the immune response in HAART play a key role in this antitumor effects, several studies have shown that HIV-PIs exert direct anti-angiogenic and anti-tumor actions. Herein we sought to evaluate whether HIV-PIs could prevent or regress cervical cancer employing a mouse model of spontaneous cervical cancer, K14-HPV/E2. To this aim we treated mice with Indinavir, Saquinavir and Ritonavir, alone or in combination. HIV-PIs hampered tumor growth and incidence by reducing vessel density and increasing of tumor apoptosis. Gene expression analysis performed on treated and untreated tumors, revealed a four-fold increase of the endogenous tissue inhibitors of metalloproteinases (TIMP2 and TIMP3), while no change in MMP-9 expression level was observed after the treatment with HIV-PIs. Studies have shown that TIMPs bind and interfere with the activation of MMPs. These results show that HIV-PIs are able to disrupt the balance between TIMPs and MMPs. In agreement with these observations, we observed a dramatic decrease of MMPs activity and a reduction of the active form of MMP-9 in treated mice compared to controls, as detected by in situ zymography and Western Blot analysis. This imbalance between MMPs and TIMPs was also critical for extracellular matrix (ECM) remodeling. Remarkably, HIV-PIs dramatically reduced tumor burden and invasiveness by increasing collagen-IV expression compared to controls. It has been shown that MMP-9 contributes to the angiogenic switch in tumors by mobilizing VEGF-A from the ECM and enabling its binding to VEGFR2. We evaluated the formation of VEGF-A-VEGR-2 complex in tumor vessels in the different treatment groups. HIV-PIs strongly reduced the amount of VEGF bound to its receptor, suggesting that HIV-PIs, by targeting MMP-9, impair the VEGF-A pathway and, consequently, inhibit tumor progression and angiogenesis. In conclusion, our data unveil for the first time that HIV-PIs have anti-angiogenic and anti-cancer effects on cervical carcinogenesis unrelated to their antiviral activity, mainly by acting on MMPs activity in tumors.
HIV-protease inhibitor exert antiangiogenic and antitumor action by disregulating the balance between TIMPs and MMPs in cervical cancer
CAPANO, STEFANIA;MAIONE, FEDERICA;MEDA, CLAUDIA MARIA;BUSSOLINO, Federico;Giraudo E.
2013-01-01
Abstract
Cervical cancer is a common malignancy worldwide. Recent studies have shown that HIV-protease inhibitors (HIV-PIs), widely used in highly active antiretroviral therapy (HAART), led to a reduced incidence and/or regression of HIV-associated tumors. Although HIV suppression and restoration of the immune response in HAART play a key role in this antitumor effects, several studies have shown that HIV-PIs exert direct anti-angiogenic and anti-tumor actions. Herein we sought to evaluate whether HIV-PIs could prevent or regress cervical cancer employing a mouse model of spontaneous cervical cancer, K14-HPV/E2. To this aim we treated mice with Indinavir, Saquinavir and Ritonavir, alone or in combination. HIV-PIs hampered tumor growth and incidence by reducing vessel density and increasing of tumor apoptosis. Gene expression analysis performed on treated and untreated tumors, revealed a four-fold increase of the endogenous tissue inhibitors of metalloproteinases (TIMP2 and TIMP3), while no change in MMP-9 expression level was observed after the treatment with HIV-PIs. Studies have shown that TIMPs bind and interfere with the activation of MMPs. These results show that HIV-PIs are able to disrupt the balance between TIMPs and MMPs. In agreement with these observations, we observed a dramatic decrease of MMPs activity and a reduction of the active form of MMP-9 in treated mice compared to controls, as detected by in situ zymography and Western Blot analysis. This imbalance between MMPs and TIMPs was also critical for extracellular matrix (ECM) remodeling. Remarkably, HIV-PIs dramatically reduced tumor burden and invasiveness by increasing collagen-IV expression compared to controls. It has been shown that MMP-9 contributes to the angiogenic switch in tumors by mobilizing VEGF-A from the ECM and enabling its binding to VEGFR2. We evaluated the formation of VEGF-A-VEGR-2 complex in tumor vessels in the different treatment groups. HIV-PIs strongly reduced the amount of VEGF bound to its receptor, suggesting that HIV-PIs, by targeting MMP-9, impair the VEGF-A pathway and, consequently, inhibit tumor progression and angiogenesis. In conclusion, our data unveil for the first time that HIV-PIs have anti-angiogenic and anti-cancer effects on cervical carcinogenesis unrelated to their antiviral activity, mainly by acting on MMPs activity in tumors.
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