Ovarian Primary and Metastatic Tumors Suppressed by Survivin Knockout or a Novel Survivin Inhibitor

Abstract

Survivin, a member of the inhibitor of apoptosis family, is upregulated in multiple cancers including ovarian cancer, but is rarely detectable in normal tissues. We previously reported that survivin promoted epithelial-to-mesenchymal transition (EMT) in ovarian cancer cells, suggesting that survivin may contribute to ovarian tumor metastasis and chemoresistance. In this study, we tested whether knockout or pharmacologic inhibition of survivin overcomes chemoresistance and suppresses tumor metastasis. The genetic loss of survivin suppressed tumor metastasis in an orthotopic ovarian cancer mouse model. To pharmacologically test the role of survivin on ovarian tumor metastasis, we treated chemo-resistant ovarian cancer cells with a selective survivin inhibitor, MX106, and found that MX106 effectively overcame chemoresistance in vitro. MX106 inhibited cell migration and invasion by attenuating the TGFb pathway and inhibiting EMT in ovarian cancer cells. To evaluate the efficacy of MX106 in inhibiting ovarian tumor metastasis, we treated an orthotopic ovarian cancer mouse model with MX106, and found that MX106 efficiently inhibited primary tumor growth in ovaries and metastasis in multiple peritoneal organs as compared with vehicle-treated control mice. Our data demonstrate that inhibition of survivin using either genetic knockout or a novel inhibitor MX106 suppresses primary ovarian tumor growth and metastasis, supporting that targeting survivin could be an effective therapeutic approach in ovarian cancer.

Promotion of ubiquitination-dependent survivin destruction contributes to xanthohumol-mediated tumor suppression and overcomes radioresistance in human oral squamous cell carcinoma

“…For example, overexpression of survivin confers insulin-like growth factor-induced lapatinib resistance in head and neck squamous carcinoma cells (HNSCC) (32). Knockdown of survivin or inhibits survivin by inhibitors suppressed metastasis of ovarian cancer (27). Furthermore, reduction of survivin expression by Brexpiprazole sensitizes glioma cells to osimertinib treatment (33).…”

STAT3, the Challenge for Chemotherapeutic and Radiotherapeutic Efficacy

“…Activation of STAT3 and survivin expression also confers resistance to chemotherapeutic agents (5-FU or cisplatin) in gastric cancer [ 123 ], hepatocellular carcinoma [ 124 ], NSCC [ 125 ] and ovarian cancer [ 104 ]. Survivin inhibitor MX106 effectively overcomes paclitaxel resistance in ovarian cancer cells [ 126 ]. In one study, STAT3 inhibition downregulated the expression of Bcl-xL, cyclin D1 and survivin, and induced apoptosis in a hepatocellular carcinoma xenograft model.…”

Combined Snail and E-cadherin Predicts Overall Survival of Cervical Carcinoma Patients: Comparison Among Various Epithelial-Mesenchymal Transition Proteins

“…Vimentin, which serves as an important intermediate filament protein in mesenchymal cells, plays a key role in the metastatic growth and invasion of tumor cells, including cervical carcinoma cells (Cheng et al, 2012;Lu et al, 2019). Survivin, a member of the inhibitors of apoptotic protein (IAP) family, which suppress apoptosis and enhance tumor cell proliferation and angiogenesis, is implicated in the EMT of some tumors (Mita et al, 2008;Breyer et al, 2016;Liu et al, 2018;Zhao et al, 2019).…”