A Luminacin D Analog HL142 Inhibits Ovarian Tumor Growth and Metastasis by Reversing EMT and Attenuating the TGFβ and FAK Pathways

Epithelial to mesenchymal transition (EMT) is known to contribute to tumor metastasis and chemoresistance. Reversing EMT using small molecule inhibitors to target EMT associated gene expression represents an effective strategy for cancer treatment. The purpose of this study is to test whether a new luminacin D analog HL142 reverses EMT in ovarian cancer (OC) and has the therapeutic potential for OC. We chemically synthesized HL142 and tested its functions in OC cells in vitro and its efficacy in inhibiting ovarian tumor growth and metastasis in vivo using orthotopic OC mouse models. We first demonstrate that ASAP1 is co-amplified and interacts with the focal adhesion kinase (FAK) protein in serous ovarian carcinoma. HL142 inhibits ASAP1 and its interaction protein FAK in highly invasive OVCAR8 and moderately invasive OVCAR3 cells. HL142 inhibits EMT phenotypic switch, accompanied by upregulating epithelial marker E-cadherin and cytokeratin-7 and downregulating mesenchymal markers vimentin, beta-catenin, and snail2 in both cell lines. Functionally, HL142 inhibits proliferation, colony formation, migration, and invasion. HL142 also sensitizes cell responses to chemotherapy drug paclitaxel treatment and inhibits ovarian tumor growth and metastasis in orthotopic OC mouse models. We further show that HL142 attenuates the TGF beta and FAK pathways in vitro using OC cells and in vivo using orthotopic mouse models.

Automated summary

This study demonstrated that a new analog HL142 can reverse EMT in ovarian cancer cells by inhibiting the interaction of ASAP1 and FAK, leading to decreased proliferation, migration, and invasion while promoting the expression of epithelial markers. HL142 also showed sensitivity to chemotherapy drug and inhibited tumor growth and metastasis in orthotopic OC mouse models by attenuating the TGF beta and FAK pathways both in vitro and in vivo.