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All-trans retinoic acid reverses epithelial-mesenchymal transition in paclitaxel-resistant cells by inhibiting nuclear factor kappa B and upregulating gap junctions.

ABSTRACT: Paclitaxel is a widely used chemotherapy drug, but development of resistance leads to treatment failure. Tumor cells that are treated with a sublethal dose of paclitaxel for a long period of time show the epithelial-mesenchymal transition (EMT) phenotype, which leads to metastasis and resistance. All-trans retinoic acid (ATRA) is always used in combination with paclitaxel and can reverse EMT in many types of cancer cells. The ability of ATRA to reverse EMT in chemoresistant cells is still unknown. In the present study, the ability of ATRA to reverse EMT in paclitaxel-resistant cells was investigated. Three colorectal cancer cell lines, HCT116, LoVo and CT26, were treated with sublethal doses of paclitaxel to create resistant cell lines. Western blotting, immunocytochemistry, and "parachute" dye-coupling assays showed that ATRA reverses EMT, inhibits nuclear factor kappa B (NF-κΒ), and upregulates gap junctions in paclitaxel-resistant cells. Scratch wound-healing and Transwell assays showed that ATRA decreases the migration and invasion abilities of paclitaxel-resistant cells. In addition, the CT26 cell line was used in the Balb/c pulmonary metastasis model to show that ATRA reduces metastasis of paclitaxel-resistant cells in vivo. Given these data, ATRA may reverse EMT by inhibiting NF-κΒ and upregulating gap junctions in paclitaxel-resistant cells.

SUBMITTER: Shi G

PROVIDER: S-EPMC6317959 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Acute lung injury (ALI) is a common clinical emergency and all‑trans retinoic acid (ATRA) can alleviate organ injury. Therefore, the present study investigated the role of ATRA in ALI. Lipopolysaccharide (LPS)‑induced ALI rats were treated with ATRA and the arterial partial pressure of oxygen (PaO2), lung wet/dry weight (W/D) ratio and protein content in the bronchial alveolar lavage fluid (BALF) were measured to evaluate the effect of ATRA on ALI rats. Alveolar macrophages were isolated from the BALF. The phagocytic function of macrophages was detected using the chicken erythrocyte phagocytosis method and flow cytometry. The viability of macrophages was measured using a Cell Counting Kit‑8 assay, and apoptosis was analyzed using a TUNEL assay and flow cytometry. The expression levels of Toll‑like receptor 4 (TLR4) and cluster of differentiation (CD)14 on the macrophage membrane were detected by immunofluorescence staining. The protein levels of TLR4, CD14, phosphorylated (p)‑65, p65, p‑IκBα and IκBα were analyzed using western blotting. The concentrations of IL‑6, IL‑1β and macrophage inflammatory protein‑2 in the plasma of rats were detected by ELISA. Macrophages were treated with IAXO‑102 (TLR4 inhibitor) to verify the involvement of CD14/TLR4 in the effect of ATRA on ALI. ATRA provided protection against LPS‑induced ALI, as evidenced by the increased PaO2 and reduced lung W/D ratio and protein content in the BALF. ATRA enhanced macrophage phagocytosis and viability and reduced apoptosis and inflammation in ALI rats. Mechanically, ATRA inhibited CD14 and TLR4 expression and NF‑κB pathway activation. ATRA enhanced macrophage phagocytosis and reduced inflammation by inhibiting the CD14/TLR4‑NF‑κB pathway in LPS‑induced ALI. In summary, ATRA inactivated the NF‑κB pathway by inhibiting the expression of CD14/TLR4 receptor in the alveolar macrophages of rats, thus enhancing the phagocytic function of macrophages in ALI rats, improving the activity of macrophages, inhibiting apoptosis, reducing the levels of inflammatory factors, and consequently playing a protective role in ALI model rats. This study may offer novel insights for the clinical management of ALI.

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All-trans retinoic acid reverses epithelial-mesenchymal transition in paclitaxel-resistant cells by inhibiting nuclear factor kappa B and upregulating gap junctions.

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