Medical Convergence Materials Commercialization Center, Gyeongsan, 38408, Republic of Korea.
Department of Pharmacology, College of Pharmacy, Catholic University of Daegu, Gyeongsan, 38430, Republic of Korea.
J Microbiol. 2020 Nov;58(11):967-977. doi: 10.1007/s12275-020-0375-y. Epub 2020 Oct 30.
Lactobacillus plantarum-derived metabolites (LDMs) increase drug sensitivity to 5-FU and antimetastatic effects in 5-FU-resistant colorectal cancer cells (HCT-116/5FUR). In this study, we evaluated the effects of LDMs on the regulation of genes and proteins involved in HCT-116/5-FUR cell proliferation and metastasis. HCT-116/5-FUR cells showed high metastatic potential, significantly reduced tight junction (TJ) integrity, including increased migration and paracellular permeability, and upregulation of claudin-1 (CLDN-1). The genetic silencing of CLDN-1 increased the sensitivity of HCT-116/5FUR to 5-FU and inhibited its metastatic potential by regulating the expression of epithelial-mesenchymal transition (EMT) related genes. Co-treatment of HCT-116/5FUR with LDMs and 5-FU suppressed chemoresistant and metastatic behavior by downregulating CLDN-1 expression. Finally, we designed LDMs-based therapeutic strategies to treatment for metastatic 5-FU-resistant colorectal cancer cells. These results suggested that LDMs and 5-FU cotreatments can synergistically target 5-FU-resistant cells, making it a candidate strategy to overcome 5-FU chemoresistance improve anticancer drug efficacy.
植物乳杆菌衍生代谢物（LDMs）增加了氟尿嘧啶耐药结直肠癌细胞（HCT-116/5FUR）对氟尿嘧啶的药物敏感性和抗转移作用。在这项研究中，我们评估了 LDMs 对调节与 HCT-116/5-FUR 细胞增殖和转移相关的基因和蛋白的影响。HCT-116/5-FUR 细胞表现出高转移潜能，显著降低紧密连接（TJ）完整性，包括迁移和旁细胞通透性增加，以及 Claudin-1（CLDN-1）上调。CLDN-1 的基因沉默通过调节上皮间质转化（EMT）相关基因的表达，增加了 HCT-116/5FUR 对 5-FU 的敏感性并抑制其转移潜能。LDMs 和 5-FU 联合处理 HCT-116/5FUR 可通过下调 CLDN-1 表达抑制耐药和转移行为。最后，我们设计了基于 LDMs 的治疗策略来治疗转移性氟尿嘧啶耐药结直肠癌细胞。这些结果表明，LDMs 和 5-FU 联合治疗可以协同靶向氟尿嘧啶耐药细胞，使其成为克服 5-FU 化疗耐药性提高抗癌药物疗效的候选策略。
