Copper deprivation enhances the chemosensitivity of pancreatic cancer to rapamycin by mTORC1/2 inhibition.
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| Abstract |
Cuproplasia, or copper-dependent cell proliferation, has been observed in varieties of solid tumors along with aberrant copper homeostasis. Several studies reported good response of patients to copper chelator assisted neoadjuvant chemotherapy, however, the internal target molecules are still undetermined. Unravel copper-associated tumor signaling would be valuable to forge new links to translate biology of copper into clinical cancer therapies. We evaluated the significance of high-affinity copper transporter-1 (CTR1) by bioinformatic analysis, and in 19 pairs of clinical specimens. Then, with the help of gene interference and chelating agent, enriched signaling pathways were identified by KEGG analysis and immunoblotting. Accompanying biological capability of pancreatic carcinoma-associated proliferation, cell cycle, apoptosis, and angiogenesis were investigated. Furthermore, a combination of mTOR inhibitor and CTR1 suppressor has been assessed in xenografted tumor mouse models. Hyperactive CTR1 was investigated in pancreatic cancer tissues and proven to as the key point of cancer copper homeostasis. Intracellular copper deprivation induced by CTR1 gene knock-down or systematic copper chelation by tetrathiomolybdate suppressed proliferation and angiogenesis of pancreatic cancer cell. PI3K/AKT/mTOR signaling pathway was suppressed by inhibiting the activation of p70(S6)K and p-AKT, and finally inhibited mTORC1 and mTORC2 after copper deprivation. Additionally, CTR1 gene silencing successfully improved the anti-cancer effect of mTOR inhibitor rapamycin. Our study reveals that CTR1 contributes to pancreatic tumorigenesis and progression, by up-regulating the phosphorylation of AKT/mTOR signaling molecules. Recovering copper balance by copper deprivation addresses as promising strategy for improved cancer chemotherapy.
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| Authors | Ruiman Geng, Nengwen Ke, Ziyao Wang, Yu Mou, Bin Xiang, Zhengkun Zhang, Xuxu Ji, Jiaqiong Zou, Dingxue Wang, Zhaoru Yin, Xubao Liu, Fang Xie, Yanan Zhao, Dan Chen, Jingying Dong, Wenbing Wu, Lihong Chen, Huawei Cai, Ji Liu |
| Journal | Chemico-biological interactions (Chem Biol Interact) Vol. 382 Pg. 110546 (Sep 01 2023) ISSN: 1872-7786 [Electronic] Ireland |
| PMID | 37290678 (Publication Type: Journal Article) |
| Copyright | Copyright © 2023 Elsevier B.V. All rights reserved. |
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