Lactobacillus -derived metabolites enhance the antitumor activity of 5-FU and inhibit metastatic behavior in 5-FU-resist
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Lactobacillus-derived metabolites enhance the antitumor activity of 5-FU and inhibit metastatic behavior in 5-FU-resistant colorectal cancer cells by regulating claudin-1 expression JaeJin An1 and Eun-Mi Ha2* 1 Medical Convergence Materials Commercialization Center, Gyeongsan 38408, Republic of Korea 2 Department of Pharmacology, College of Pharmacy, Catholic University of Daegu, Gyeongsan 38430, Republic of Korea
(Received Jul 16, 2020 / Revised Sep 7, 2020 / Accepted Sep 15, 2020)
Lactobacillus plantarum-derived metabolites (LDMs) increase drug sensitivity to 5-FU and antimetastatic effects in 5-FUresistant 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 HCT116/5FUR 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. Keywords: colorectal cancer, HCT-116, 5-FU, chemoresistant, Lactobacillus, metastasis, tight junction, CLDN-1, combination therapy Introduction Colorectal cancer (CRC) is the third-most common cancer worldwide and is ranked as the second leading cause of cancer-related deaths (Siegel et al., 2017). A recent report has predicted that the incidence of CRC in developing countries will continue to increase until at least 2030 and that the global economic burden resulting from CRC will increase by more than 60% (Dekker et al., 2019). The conventional treatment *For correspondence. E-mail: [email protected]; Tel.: +82-53-850-3612; Fax: +82-53-850-3602 Copyright G2020, The Microbiological Society of Korea
for CRC patients is a combination of surgery and chemotherapy that includes 5-fluorouracil (5-FU) (Aparicio, 2011). However, a significant proportion of CRC patients become resistant to 5-FU, which is a major cause of CRC treatment failure (Han et al., 2007). Furthermore, approximately 50% of all CRC patients develop metastasis during chemotherapy (Van Der Jeught et al., 2018); the average survival for these patients is 30 months (Siegel et al., 2017). Chemoresistance and metastasis are related to the high recurrence and mortality rates in CRC. Intercellular adhesion is closely involved in the process of the invasion and metastasis of cancer
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