iridoids and Gallbladder-Neoplasms

Uncoupling protein 2 (UCP2) is a mitochondrial anion carrier which plays a key role in energy homeostasis. UCP2 is deregulated in several human cancers and has been suggested to regulate cancer metabolism. However, the role of UCP2 in gallbladder cancer has not been defined. Using clinical samples, we found highly expressed UCP2 in gallbladder cancer tissues, and higher expression levels of UCP2 correlated with worse clinical characteristics. To study whether UCP2 promotes gallbladder cancer growth, UCP2 stable knockdown cells were generated, and cell proliferation was suppressed in these knockdown cells. Further studies demonstrated that glycolysis was inhibited and IKKβ, as well as the downstream signaling molecules NF-κB/FAK/β-catenin, were downregulated in UCP2 knockdown cells. More importantly, gallbladder cancer cells became sensitive to gemcitabine treatments when UCP2 was inhibited. UCP2 knockdown suppressed the activation of the NF-κB/β-catenin axis and promoted the increases in mitochondrial ROS in gallbladder cancer cells exposed to gemcitabine treatments. The UCP2 inhibitor genipin suppressed xenograft tumor growth and sensitized grafted tumors to gemcitabine treatments. These results suggest targeting UCP2 as a novel therapeutic strategy for the treatment of gallbladder cancer.

Topics: Animals; Antineoplastic Agents; beta Catenin; Cell Line, Tumor; Cisplatin; Deoxycytidine; Drug Resistance, Neoplasm; Gallbladder Neoplasms; Gemcitabine; Gene Expression Regulation, Neoplastic; Gene Knockdown Techniques; Humans; Iridoids; Male; Mice; Mice, Nude; Mitochondria; Neoplasms, Experimental; NF-kappa B; Reactive Oxygen Species; Uncoupling Protein 2; Up-Regulation