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Ixazomib promotes CHOP-dependent DR5 induction and apoptosis in colorectal cancer cells

Dan Yue1, Xun Sun2

  • 1a Department of Laboratory Medicine , ShengJing Hospital of China Medical University , Shenyang , China.

Cancer Biology & Therapy
|October 26, 2018
PubMed
Abstract

Insights

Ixazomib induces cancer cell death by upregulating DR5, a protein crucial for apoptosis. This proteasome inhibitor shows promise in colorectal cancer treatment, especially when combined with TRAIL therapy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Ixazomib is a proteasome inhibitor with demonstrated anti-tumor efficacy in various cancers.
  • The precise mechanism of ixazomib's anti-tumor effects in colorectal cancer (CRC) cells is not fully understood.

Purpose of the Study:

  • To elucidate the mechanism of ixazomib's anti-tumor activity in colorectal cancer cells.
  • To investigate the role of DR5 and CHOP in ixazomib-induced apoptosis.

Main Methods:

  • Cell viability assays (MTS) and flow cytometry were used to assess ixazomib's effects.
  • Western blotting, RT-PCR, and ChIP assays were employed to analyze molecular changes.
  • Xenograft experiments evaluated in vivo anti-tumor efficacy.

Main Results:

  • Ixazomib treatment induced C/EBP homologous protein (CHOP)-dependent death receptor 5 (DR5) upregulation in CRC cells, independent of p53 status.
  • DR5 expression was essential for ixazomib-induced apoptosis.
  • Ixazomib synergized with TRAIL to enhance apoptosis through DR5.

Conclusions:

  • Ixazomib inhibits CRC cell growth via CHOP-dependent DR5 induction and subsequent apoptosis.
  • Ixazomib sensitizes colorectal cancer cells to TRAIL-mediated apoptosis.
  • DR5 induction may serve as a predictive biomarker for ixazomib sensitivity.
Keywords:
CHOPIxazomibTRAILdeath receptor 5extrinsic apoptotic pathway

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