GGPP as a driver of esophageal squamous cell carcinoma progression via protein prenylation: Therapeutic potential of zoledronic acid repurposing.

Abstract

e16104 Background: Esophageal cancer is a prevalent malignant tumor of the digestive system, with its development closely related to metabolic reprogramming. Emerging evidence implicates dysregulated cholesterol biosynthesis in ESCC pathogenesis, yet the specific role of geranylgeranyl pyrophosphate (GGPP), a critical intermediate metabolite, remains poorly defined. This study investigates how GGPP drives ESCC progression through protein prenylation-dependent mitochondrial reprogramming and evaluates the therapeutic potential of targeting GGPP synthesis using zoledronic acid (ZA), a clinically approved bisphosphonate for osteoporosis. Methods: The oncogenic role of GGPP was systematically investigated through genetic manipulation of GGPS1 (the rate-limiting enzyme for GGPP synthesis) and pharmacological inhibition with ZA. Transcriptomic profiling and immunohistochemistry were performed on ESCC patient tissues. Functional assays including CCK-8, colony formation, nude mouse xenograft models and seahorse metabolic analysis assessed the impact of GGPP depletion on cell proliferation and mitochondrial oxidative phosphorylation (OXPHOS). GGPP rescue experiments validated metabolite-specific effects. Candidate prenylated proteins were identified through LC-MS and validated by Western blotting. The therapeutic efficacy of ZA was assessed in xenograft-bearing nude mice via tail vein injection, with tumor growth monitored by caliper measurements and endpoint analyses including tumor weight and immunohistochemistry. Results: Transcriptomic analysis revealed significant upregulation of cholesterol biosynthesis genes in ESCC tissues, with GGPS1 expression positively correlating with disease progression. GGPS1 knockdown markedly suppressed ESCC cell proliferation and tumor growth in xenograft models, accompanied by reduced Ki67 expression. Mechanistically, GGPP depletion disrupted protein prenylation, leading to impaired mitochondrial OXPHOS and fatty acid oxidation. Exogenous GGPP supplementation fully rescued the proliferative defects caused by GGPS1 knockdown, confirming GGPP as the critical effector metabolite. Importantly, pharmacological inhibition of GGPP synthesis with ZA significantly inhibited tumor growth in xenograft models, with no apparent toxicity. Conclusions: This study identifies GGPP as a pivotal oncometabolite driving ESCC progression through prenylation-dependent maintenance of mitochondrial OXPHOS. Targeting the GGPP synthesis pathway represents a promising therapeutic strategy for ESCC. The demonstrated preclinical efficacy of zoledronic acid provides strong rationale for clinical repurposing of this FDA-approved drug in ESCC patients, offering a readily translatable therapeutic approach for this aggressive malignancy.