RIPK1 Binds MCU to Mediate Induction of Mitochondrial Ca2+ Uptake and Promotes Colorectal Oncogenesis

Cancer Res. 2018 Jun 1;78(11):2876-2885. doi: 10.1158/0008-5472.CAN-17-3082. Epub 2018 Mar 12.

Abstract

The receptor-interacting protein kinase 1 (RIPK1) is an essential signaling molecule in pathways for cell survival, apoptosis, and necroptosis. We report here that RIPK1 is upregulated in human colorectal cancer and promotes cell proliferation when overexpressed in a colon cancer cell line. RIPK1 interacts with mitochondrial Ca2+ uniporter (MCU) to promote proliferation by increasing mitochondrial Ca2+ uptake and energy metabolism. The ubiquitination site of RIPK1 (RIPK1-K377) was critical for this interaction with MCU and function in promoting cell proliferation. These findings identify the RIPK1-MCU pathway as a promising target to treat colorectal cancer.Significance: RIPK1-mediated cell proliferation through MCU is a central mechanism underlying colorectal cancer progression and may prove to be an important therapeutic target for colorectal cancer treatment. Cancer Res; 78(11); 2876-85. ©2018 AACR.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / physiology
  • Calcium / metabolism*
  • Calcium Channels / metabolism*
  • Carcinogenesis / metabolism*
  • Carcinogenesis / pathology
  • Cell Line, Tumor
  • Cell Proliferation / physiology
  • Colorectal Neoplasms / metabolism*
  • Colorectal Neoplasms / pathology
  • Energy Metabolism / physiology
  • HT29 Cells
  • Humans
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Mitochondria / metabolism*
  • Receptor-Interacting Protein Serine-Threonine Kinases / metabolism*
  • Ubiquitination / physiology
  • Up-Regulation / physiology

Substances

  • Calcium Channels
  • RIPK1 protein, human
  • Receptor-Interacting Protein Serine-Threonine Kinases
  • Calcium