Ras inhibition by zoledronic acid effectively sensitizes cervical cancer to chemotherapy

Aberrant activation of Ras is common in several human cancers, including cervical cancer. In this study, we show that Ras function can be inhibited by zoledronic acid (ZA) owing to its ability in inhibiting protein prenylation. Using in-vitro cell culture system and an in-vivo xenograft mouse model, the effects of ZA on cervical cancer cell growth and survival were determined. The molecular mechanisms of ZA's action were analyzed focusing on prenylation and its downstream signaling pathways. ZA inhibited proliferation and induced apoptosis of multiple cervical cancer cell lines regardless of their cellular origin and genetic profiling. The combination of ZA with paclitaxel or doxorubicin was superior to a single drug alone in cervical cancer in vitro and in vivo. Notably, complete inhibition of cervical cancer growth was observed in the combination groups. Mechanistically, ZA inhibited prenylation of oncoproteins. Ras activity was largely affected by ZA in a prenylation-dependent manner. Consistently, Ras-mediated signaling pathways such as Raf/ERK and AKt/mTOR were deactivated in cervical cancer cells exposed to ZA. Overexpression of constitutively active Ras reversed the inhibitory effects of ZA, confirming that Ras inhibition was required for the action of ZA in cervical cancer. Despite extensive efforts, there has been limited progress in the development of direct Ras inhibitors. Our findings suggest that ZA inhibits Ras activity. Our work provides fundamental evidence to repurpose ZA for the treatment of cervical cancer.