Inhibition of STX17–SNAP29–VAMP8 complex formation by costunolide sensitizes ovarian cancer cells to cisplatin via the AMPK/mTOR signaling pathway

Ovarian cancer (OC) is the most common gynecological malignancy. Chemotherapy failure is a major challenge in OC treatment. Targeting autophagy is a promising strategy to enhance the cytotoxicity of chemotherapeutic agents. In this study, we found that costunolide (CTD) inhibits autophagic flux and exhibits high therapeutic efficacy for OC treatment in an in vitro model. Mechanistically, CTD inactivates AMPK/mTOR signaling to inhibit autophagy initiation at the early stage and blocks mTORC1-dependent autophagosome-lysosome fusion at the late stage during autophagy by disrupting SNARE complex (STX17-SNAP29-VAMP8) formation, resulting in lethal autophagy arrest in OC cells. Furthermore, CTD sensitizes OC cells to cisplatin (CDDP) by blocking CDDP-induced autophagy both in vitro and in vivo. Together, our data provide novel mechanistic insights into CTD-induced autophagy arrest and suggest a new autophagy inhibitor for effective treatment of OC.