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Abstract: Objective.: Previous studies have demonstrated the pivotal roles of matrix metalloproteinases (MMPs) in cervical cancer progression. Tissue inhibitor of metalloproteinases-3 (TIMP-3) can inhibit all of MMPs, and its overexpression can retard many kinds of tumor growth. Especially, a potent bystander effect would make it to be more advisable for treating cervical cancer whose primary growth pattern is to invade adjacent structures. These characters prompted the authors to explore its further applicability in human cervical cancer. Methods.: We constructed a replication deficient adenoviral vector carrying TIMP-3 (Ad-TIMP-3). It was transferred into different cervical cancer cell lines in vitro and was injected into the tumor xenografts of nude mice in vivo. Results.: Overexpression of TIMP-3 by adenovirus vector arrested cervical cancer cells in G2/M phase. It also promoted growth inhibition of cancer cells by bystander effects. Ad-TIMP-3 infection produced a more potent cell killing effect than Ad-p53 (P <0.05). A synergic effect was observed when Ad-TIMP-3 and cisplatin (cDDP) were used in combination (D <1). In vivo, Ad-TIMP-3 could inhibit cervical cancer xenografts growth. Compared with Ad-TIMP-3 and cDDP groups, tumor growth in Ad-TIMP-3 combined with cDDP group was inhibited more significantly (P <0.05). Conclusion.: These findings indicated that Ad-TIMP-3 bear a therapeutic potential for cervical cancer. [Copyright &y& Elsevier]

Abstract: Purpose/Objective. : To investigate whether exogenous PUMA expression suppresses the growth of drug-resistant choriocarcinoma cells and sensitizes them to chemotherapeutic agents. Methods. : An adenovirus expressing PUMA (Ad-PUMA), alone or in combination with chemotherapeutic agents( 5-FU, vp16, MTX), was used to treat drug-resistant choriocarcinoma cells jeg-3/vp16 and parental jeg-3. The growth inhibitory and proapoptotic effects of Ad-PUMA both in vitro and in vivo were examined. The mechanisms of PUMA-mediated growth suppression and apoptosis were investigated by an analysis of caspase 3 activation and the change of mitochondrial membrane potential. The levels of PUMA, p53 and caspase 3 were detected by Western blotting. Result. : PUMA was expressed lower in jeg-3/vp16 than in jeg-3. jeg-3/vp16 responded much less sensitively to 5-FU and vp16 treatment than jeg-3, though PUMA was up-regulated in both cells. Exogenous PUMA expression resulted in potent growth suppression of jeg-3/vp16 and jeg-3 through induction of apoptosis. Ad-PUMA sensitized jeg-3 and jeg-3/vp16 to chemotherapeutic agents. When Ad-PUMA 10MOI and 5-FU, vp16 or MTX were combined respectively, IC50 of drugs decreased by 8.66-, 18.66- and 13.06-fold compared with those treated by anticancer drugs alone in jeg-3/vp16, while in jeg-3, IC50 decreased only by 1.80-, 1.78- and 2.76-fold. Ad-PUMA restored the sensitivity of choriocarcinoma cells to chemotherapeutic agents by enhancing apoptosis induced by anticancer drugs. Similar results could be observed in vivo. Xenograft tumors were inhibited by Ad-PUMA or vp16. In the drug-resistant group, the inhibitory rate increased from 14.57% to 78.93% in vp16 and vp16 combined with Ad-PUMA subgroups. While in the parental group, the inhibitory rate increased but slightly, from 66.39% to 71.56%. Conclusion. : PUMA is an important player in the therapeutic responses to chemotherapeutic agents of choriocarcinoma cells. In addition to its role in inhibiting tumor growth, low dose of Ad-PUMA significantly restored the sensitivity of choriocarcinoma cells to chemotherapeutic agents in vitro and in vivo. Exogenous PUMA is potentially useful as a sensitizer in treating drug-resistant choriocarcinoma. [Copyright &y& Elsevier]

Abstract: Objectives: Arsenic trioxide (As2O3) was found to induce apoptosis in certain types of cancer cells including acute promyelocytic leukemia, and recently in solid tumors. We have previously demonstrated that As2O3 has a therapeutic effect on cervical cancer by apoptosis promotion in vitro and in vivo. Here we further our study on the role of arsenic trioxide in regulating invasive activity of cervical cancer cells in vitro and in vivo. Methods: The effects of As2O3 on human cervical cancer cell lines (HeLa, SiHa, Caski) adhesion, migration and invasion were observed by means of cell adhesion test, cell migration test and cell invasion test. The effects of As2O3 on p-IκB, MMP-2, E-cadherin, caveolin-1 and β-catenin protein expressions of tumor cells were determined by Western blot. In addition, the effects of As2O3 on NF-κB activity of tumor cells were analyzed by immunoblot in whole lysates, cytosol and nucleus, respectively. In animal experiments, cervical cancer cells TC-1 were injected into tail veins of C57BL/6 mice and then the mice were treated by intraperitoneal injection of different doses As2O3. Lung weights and the foci on the surface of lungs were measured. Results: As2O3 inhibited attachment of tumor cells to Fibronectin and Matrigel, reduced cell motility and inhibited tumor invasion potential. As2O3 treatment also resulted in a positive regulation of caveolin-1, upregulation of E-cadherin and decreased activity of β-catenin, NF-κB and NF-κB-regulated gene MMP-2. In animal experiments, lung weights in PBS group (0.31±0.07 g) were significantly elevated compared with those in As2O3-treated groups (0.21±0.03 g and 0.17±0.03 g) also As2O3 reduced number of metastatic lesions of lungs (15.4±3.5 vs. 8.3±2.0 and 6.3±2.3) in a dose-dependent manner. Conclusions: This study is the first to report the effectiveness of As2O3 as an inhibitor of cervical cancer invasion both in vitro and in vivo, suggesting a potential clinical application of As2O3 in cervical cancer therapies combining apoptosis induction and metastasis inhibition. [Copyright &y& Elsevier]

We previously identified a cell cycle-dependent periodic subcellular distribution of cancer metastasis-associated antigen 1 (MTA1) and unraveled a novel role of MTA1 in inhibiting spindle damage-induced spindle assembly checkpoint (SAC) activation in cancer cells. However, the more detailed subcellular localization of MTA1 in mitotic cells and its copartner in SAC regulation in cancer cells are still poorly understood. Here, through immunofluorescent colocalization analysis of MTA1 and alpha-tubulin in mitotic cancer cells, we reveal that MTA1 is dynamically localized to the spindle apparatus throughout the entire mitotic process. We also demonstrated a reversible upregulation of MTA1 expression upon spindle damage-induced SAC activation, and time-lapse imaging assays indicated that MTA1 silencing delayed the mitotic metaphase-anaphase transition in cancer cells. Further investigation revealed that MTA1 interacts and colocalizes with Translocated Promoter Region (TPR) on spindle microtubules in mitotic cells, and this interaction is attenuated on SAC activation. TPR is well-implicated in SAC regulation via binding the MAD1-MAD2 complex, however, no interactions between MTA1 and MAD1 or MAD2 were detected in our coimmunoprecipitation (co-IP) assays, suggesting that the MTA1-TPR may represent a distinct SAC-associated complex separate from the previously reported TPR-MAD1/MAD2 complex. Our data provide new insights into the subcellular localization and molecular function of MTA1 in SAC regulation in cancer, and indicate that intervention of the MTA1-TPR interaction may be effective to modulate SAC and hence chromosomal instability (CIN) in tumorigenesis. • MTA1 localizes to the mitotic spindle apparatus during mitosis. • MTA1 is upregulated on spindle damage-induced SAC activation. • MTA1 silencing delays the mitotic metaphase-anaphase transition. • MTA1 interacts and colocalizes with TPR on the spindle apparatus. • MTA1-TPR interaction is weakened upon SAC activation. [ABSTRACT FROM AUTHOR]