Open Access

Novel quinazolinone MJ‑33 induces AKT/mTOR‑mediated autophagy‑associated apoptosis in 5FU‑resistant colorectal cancer cells

  • Authors:
    • Hai‑Anh Ha
    • Jo‑Hua Chiang
    • Fuu‑Jen Tsai
    • Da‑Tian Bau
    • Yu‑Ning Juan
    • Yu‑Hsiang Lo
    • Mann‑Jen Hour
    • Jai‑Sing Yang
  • View Affiliations

  • Published online on: December 3, 2020     https://doi.org/10.3892/or.2020.7882
  • Pages: 680-692
  • Copyright: © Ha et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Novel quinazolinone compounds have been studied in the field of drug discovery for a long time. Among their broad range of pharmacological effects, certain compounds effectively inhibit cancer cell proliferation. MJ‑33 is a quinazolinone derivative with proposed anticancer activities that was synthesized in our laboratory. The present study aimed to evaluate the anticancer activity of MJ‑33 in fluorouracil (5FU)‑resistant colorectal cancer cells (HT‑29/5FUR) and to investigate the underlying molecular mechanisms. The cell viability assay results indicated that HT‑29/5FUR cell viability was inhibited by MJ‑33 treatment in a concentration‑dependent manner compared with the control group. The cellular morphological alterations observed following MJ‑33 treatment indicated the occurrence of apoptosis and autophagy, as well as inhibition of cell proliferation in a time‑dependent manner compared with the control group. The acridine orange, LysoTracker Red and LC3‑green fluorescent protein staining results indicated that MJ‑33 treatment significantly induced autophagy compared with the control group. The DAPI/TUNEL dual staining results demonstrated increased nuclear fragmentation and condensation following MJ‑33 treatment compared with the control group. The Annexin V apoptosis assay and image cytometry analysis results demonstrated a significant increase in apoptotic cells following MJ‑33 treatment compared with the control group. The western blotting results demonstrated markedly decreased Bcl‑2, phosphorylated (p)‑BAD, pro‑caspase‑9 and pro‑caspase‑3 expression levels, and notably increased cytochrome c and apoptotic peptidase activating factor 1 expression levels following MJ‑33 treatment compared with the control group. Moreover, the expression levels of autophagy‑related proteins, including autophagy related (ATG)‑5, ATG‑7, ATG‑12, ATG‑16, p62 and LC3‑II, were increased following MJ‑33 treatment compared with the control group. Furthermore, MJ‑33‑treated HT‑29/5FUR cells displayed decreased expression levels of p‑AKT and p‑mTOR compared with control cells. The results suggested that MJ‑33‑induced apoptosis was mediated by AKT signaling, and subsequently modulated via the mitochondria‑dependent signaling pathway. Therefore, the results suggested that suppression of AKT/mTOR activity triggered autophagy in the HT‑29/5FUR cell line. In summary, the results indicated that MJ‑33 inhibited HT‑29/5FUR cell viability, and induced apoptosis and autophagy via the AKT/mTOR signaling pathway. The present study may provide novel insight into the anticancer effects and mechanisms underlying MJ‑33 in 5FU‑resistant colorectal cancer cells.
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February-2021
Volume 45 Issue 2

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Spandidos Publications style
Ha HA, Chiang JH, Tsai FJ, Bau DT, Juan YN, Lo YH, Hour MJ and Yang JS: Novel quinazolinone MJ‑33 induces AKT/mTOR‑mediated autophagy‑associated apoptosis in 5FU‑resistant colorectal cancer cells. Oncol Rep 45: 680-692, 2021
APA
Ha, H., Chiang, J., Tsai, F., Bau, D., Juan, Y., Lo, Y. ... Yang, J. (2021). Novel quinazolinone MJ‑33 induces AKT/mTOR‑mediated autophagy‑associated apoptosis in 5FU‑resistant colorectal cancer cells. Oncology Reports, 45, 680-692. https://doi.org/10.3892/or.2020.7882
MLA
Ha, H., Chiang, J., Tsai, F., Bau, D., Juan, Y., Lo, Y., Hour, M., Yang, J."Novel quinazolinone MJ‑33 induces AKT/mTOR‑mediated autophagy‑associated apoptosis in 5FU‑resistant colorectal cancer cells". Oncology Reports 45.2 (2021): 680-692.
Chicago
Ha, H., Chiang, J., Tsai, F., Bau, D., Juan, Y., Lo, Y., Hour, M., Yang, J."Novel quinazolinone MJ‑33 induces AKT/mTOR‑mediated autophagy‑associated apoptosis in 5FU‑resistant colorectal cancer cells". Oncology Reports 45, no. 2 (2021): 680-692. https://doi.org/10.3892/or.2020.7882