Open Access

All‑trans‑retinoic acid induces RARB‑dependent apoptosis via ROS induction and enhances cisplatin sensitivity by NRF2 downregulation in cholangiocarcinoma cells

  • Authors:
    • Siriwoot Butsri
    • Veerapol Kukongviriyapan
    • Laddawan Senggunprai
    • Sarinya Kongpetch
    • Auemduan Prawan
  • View Affiliations

  • Published online on: April 14, 2022     https://doi.org/10.3892/ol.2022.13299
  • Article Number: 179
  • Copyright: © Butsri et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )


Abstract

All‑trans‑retinoic acid (ATRA) has been clinically used to treat acute promyelocytic leukemia and is being studied to treat other types of cancer; however, the therapeutic role and mechanism of ATRA against cholangiocarcinoma (CCA) remain unclear. The present study investigated the cytotoxic effect and underlying mechanisms of ATRA on CCA cell lines. Cell viability was evaluated by sulforhodamine B assay. Intracellular reactive oxygen species (ROS) levels were assessed by dihydroethidium assay. Apoptosis analysis was performed by flow cytometry. The pathways of apoptotic cell death induction were examined using enzymatic caspase activity assay. Proteins associated with apoptosis were evaluated by western blotting. The effects on gene expression were analyzed by reverse transcription‑quantitative PCR analysis. ATRA induced a concentration‑ and time‑dependent toxicity in CCA cells. Furthermore, when the cytotoxicity of ATRA against retinoic acid receptor (RAR)‑deficient cells was assessed, it was revealed that ATRA cytotoxicity was RARB‑dependent. Following ATRA treatment, there was a significant accumulation of cellular ROS and ATRA‑induced ROS generation led to an increase in the expression levels of apoptosis‑inducing proteins and intrinsic apoptosis. Pre‑treatment with ROS scavengers could diminish the apoptotic effect of ATRA, suggesting that ROS and mitochondria may have an essential role in the induction of apoptosis. Furthermore, following ATRA treatment, an increase in cellular ROS content was associated with suppressing nuclear factor erythroid 2‑related factor 2 (NFE2L2 or NRF2) and NRF2‑downstream active genes. ATRA also suppressed cisplatin‑induced NRF2 expression, suggesting that the enhancement of cisplatin cytotoxicity by ATRA may be associated with the downregulation of NRF2 signaling. In conclusion, the results of the present study demonstrated that ATRA could be repurposed as an alternative drug for CCA therapy.
View Figures
View References

Related Articles

Journal Cover

June-2022
Volume 23 Issue 6

Print ISSN: 1792-1074
Online ISSN:1792-1082

Sign up for eToc alerts

Recommend to Library

Copy and paste a formatted citation
x
Spandidos Publications style
Butsri S, Kukongviriyapan V, Senggunprai L, Kongpetch S and Prawan A: All‑<em>trans</em>‑retinoic acid induces RARB‑dependent apoptosis via ROS induction and enhances cisplatin sensitivity by NRF2 downregulation in cholangiocarcinoma cells. Oncol Lett 23: 179, 2022
APA
Butsri, S., Kukongviriyapan, V., Senggunprai, L., Kongpetch, S., & Prawan, A. (2022). All‑<em>trans</em>‑retinoic acid induces RARB‑dependent apoptosis via ROS induction and enhances cisplatin sensitivity by NRF2 downregulation in cholangiocarcinoma cells. Oncology Letters, 23, 179. https://doi.org/10.3892/ol.2022.13299
MLA
Butsri, S., Kukongviriyapan, V., Senggunprai, L., Kongpetch, S., Prawan, A."All‑<em>trans</em>‑retinoic acid induces RARB‑dependent apoptosis via ROS induction and enhances cisplatin sensitivity by NRF2 downregulation in cholangiocarcinoma cells". Oncology Letters 23.6 (2022): 179.
Chicago
Butsri, S., Kukongviriyapan, V., Senggunprai, L., Kongpetch, S., Prawan, A."All‑<em>trans</em>‑retinoic acid induces RARB‑dependent apoptosis via ROS induction and enhances cisplatin sensitivity by NRF2 downregulation in cholangiocarcinoma cells". Oncology Letters 23, no. 6 (2022): 179. https://doi.org/10.3892/ol.2022.13299