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  • Acknowledgments br Introduction Prostate cancer is the first

    2024-06-11

    Acknowledgments
    Introduction Prostate cancer is the first leading cause of cancer-related deaths among males in the UK and the second in the US. Despite recent advances in surgery, radiation, medical management and screening, prostate cancer patients suffer high morbidity and mortality and significant treatment-associated complications [1]. Chemoprevention has the potential to reduce cancer formation, and decrease the morbidity and mortality of many types of cancer including prostate cancer [1], [2], [3]. Among all chemopreventive agents, natural products and naturally occurring compounds have received increasing attention in recent years for the discovery and development of novel chemopreventive or anti-cancer agents [2], [3]. ATP citrate lyase (ACLY) is a key enzyme recently shown to be crucial for cancer cell metabolism. ACLY is a metabolic enzyme responsible for the conversion of mitochondria-derived citrate into acetyl CoA, a precursor for the synthesis of both fatty acids and mevalonate [4], [5], [6]. Both fatty Cisplatin synthesis and mevalonate synthesis are associated with cancer cell growth and transformation [4], [5], [6], [7], [8], [9]. Activated ACLY signaling is associated with many human cancer types including prostate cancer, lung adenocarcinoma, leukemia, glioblastomas, ovarian cancer, and liver cancer [4], [5], [6], [7], [8], [9], [10], [11], [12], [13], [14], [15], [16]. It is believed that specific blockade of ACLY signaling may have therapeutic potential for human cancers [4], [5], [6], [7], [8], [9], [10], [11], [12], [13], [14], [15], [16]. However, such anti-ACLY agents deemed suitable for and applicable to humans have yet to be developed. The cucumber (Cucumis sativus L) is a member of the Cucurbitaceae family, which includes the melons, squash and pumpkins. Cucumbers are commercially cultivated as a seasonal vegetable crop worldwide [17], [18]. Cucurbitacins (CUs) are one of the main bioactive compounds found in cucumber. CUs are a class of highly oxidized tetracyclic triterpenoids and have been used for their potential antidiabetic, lipid-lowering and antioxidant activities since ancient times [17], [18]. Structurally, CUs are characterized by a tetracyclic cucurbitane nucleus skeleton, namely, 9β-methyl-19-nor lanosta-5-enea, which is traditionally divided arbitrarily into twelve categories, incorporating CUs A-T [17], [18]. In recent years, several types of CUs have been shown to inhibit proliferation and induce apoptosis and autophagy in human cancer using in vitro and in vivo models [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32], [33], [34], [35], [36]. Cucurbitacin B (CuB) is one of the most abundant forms of CU and one of the best studied members of the CU family of compounds [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32], [33], [34]. CuB-induced apoptotic cell death has been reported in human breast cancer cells [19], [20], [26], [28], [30], [31], [33], pancreatic cancer cells [21], [22], hepatocellular carcinoma cells [23], [24], lung cancer cells [25], cervical cancer cells [26], primary glioblastoma cells [26], skin cancer cells [26], renal carcinoma cells [29], laryngeal squamous cell carcinoma cells [32] and colon cancer cells [26], [30]. The mechanism behind the anticancer effect of CuB is not fully understood, but several signaling molecules have been shown to be targets for the anticancer activity of CuB, including the signal transducer and activator of transcription (STAT), cyclooxygenase-2, BRCA1, and the p34CDC2/Cyclin B1 complex [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32], [33], [34]. Among all CUs, only Cucurbitacin E [35] and 23,25-dihydrocucurbitacin F [36] have been shown to harbor anti-proliferative activity against human prostate cancer cells, and the potential anti-tumor and chemopreventive activity of CuB in human prostate cancer has not been investigated. Here, we identified for the first time the potent anti-cancer activity of CuB against human prostate cancer cells, and, more importantly, its potent chemopreventive activity in a prostate cancer in vivo model. Further mechanistic investigations reveal a novel anti-cancer mechanism of CuB via the inhibition of ATP citrate lyase signaling in prostate cancer models.