Synthetic lethality in human bladder cancer cells by curcumin via concurrent Aurora A inhibition and autophagy induction

Ya-Wen Fan; I-Ching Lu; Man-Yuan Hsu; Wan-Ting Kuo; Shan-Ying Wu; Sheng-Hui Lan; Pao-Yuan Wang; Ching-Ying Chen; Hsiao-Sheng Liu; Chun-Li Su

doi:10.1016/j.jnutbio.2023.109438

Synthetic lethality in human bladder cancer cells by curcumin via concurrent Aurora A inhibition and autophagy induction

J Nutr Biochem. 2023 Nov:121:109438. doi: 10.1016/j.jnutbio.2023.109438. Epub 2023 Sep 2.

Authors

Affiliations

¹ Department of Human Development and Family Studies, National Taiwan Normal University, Taipei, Taiwan.
² Graduate Program of Nutrition Science, School of Life Science, National Taiwan Normal University, Taipei, Taiwan.
³ Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
⁴ Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan, Taiwan; Department of Microbiology and Immunology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
⁵ Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan, Taiwan; Department of Life Sciences and Institute of Genome Sciences, National Yang Ming Chiao Tung University, Taipei, Taiwan.
⁶ Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan, Taiwan; Center of Infectious Disease and Signaling Research Center, College of Medicine, National Cheng Kung University, Tainan, Taiwan; Master of Science Program in Tropical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
⁷ Department of Human Development and Family Studies, National Taiwan Normal University, Taipei, Taiwan; Graduate Program of Nutrition Science, School of Life Science, National Taiwan Normal University, Taipei, Taiwan. Electronic address: chunlisu@ntnu.edu.tw.

PMID: 37666476
DOI: 10.1016/j.jnutbio.2023.109438

Abstract

Combination therapies to induce mixed-type cell death and synthetic lethality have the potential to overcome drug resistance in cancer. In this study, we demonstrated that the curcumin-enhanced cytotoxicity of cisplatin/carboplatin in combination with gemcitabine was associated with Aurora A suppression-mediated G2/M arrest, and thus apoptosis, as well as MEK/ERK-mediated autophagy in human bladder cancer cells. Animal study data confirmed that curcumin combined with cisplatin/gemcitabine reduced tumorigenesis of xenograft in mice and this phenomenon was associated with elevated expressions of p-ERK and reduced p-Aurora A in tumors. Gene analyses using data repositories further revealed that reduced Aurora A expression alone did not significantly elevate the sensitivity of human bladder carcinoma cells to these anticancer drugs. Unlike other major cancer types, human bladder urothelial carcinoma tissue coexpressed higher AURKA and lower MAP1LC3B than normal tissue, and reduced Aurora A and induction of autophagy have been clinically associated with a better prognosis in patients with early but not advanced stage bladder cancer. Therefore, our results suggest that treatment strategies can utilize the synthetic lethal pair to concurrently suppress oncogenic Aurora A and induce autophagy by coadministrating curcumin with anticancer drugs for early-stage bladder cancer with high expression of Aurora A.

Keywords: Aurora A; Autophagy; Curcumin; Human bladder cancer; Synthetic lethality.