Sulindac sulfone inhibits the mTORC1 pathway in colon cancer cells by directly targeting voltage-dependent anion channel 1 and 2

Biochem Biophys Res Commun. 2018 Nov 10;505(4):1203-1210. doi: 10.1016/j.bbrc.2018.10.050. Epub 2018 Oct 14.


Sulindac sulfone is a metabolite of sulindac, a non-steroidal anti-inflammatory drug (NSAID), without anti-inflammatory ability. However, sulindac sulfone has been reported to significantly reduce polyps in patients with colorectal adenomatous polyposis in clinical trials. Thus, sulindac sulfone is expected to be useful for the chemoprevention of neoplasia with few side effects related to anti-inflammatory ability. To date, the molecular targets of sulindac sulfone have not yet fully investigated. Therefore, in order to newly identify sulindac sulfone-binding proteins, we generated sulindac sulfone-fixed FG beads and purified sulindac sulfone-binding proteins from human colon cancer HT-29 cells. we identified mitochondrial outer membrane proteins voltage-dependent anion channel (VDAC) 1 and VDAC2 as novel molecular targets of sulindac sulfone, and sulindac sulfone directly bound to both VDAC1 and VDAC2. Double knockdown of VDAC1 and VDAC2 by siRNA inhibited growth and arrested the cell cycle at G1 phase in HT-29 cells. Depletion of VDAC1 and VDAC2 also inhibited the mTORC1 pathway with a reduction in cyclin D1. Interestingly, these effects were consistent with those of sulindac sulfone against human colon cancer cells, suggesting that sulindac sulfone negatively regulates the function of VDAC1 and VDAC2. In the present study, our data suggested that VDAC1 and VDAC2 are direct targets of sulindac sulfone which suppresses the mTORC1 pathway and induces G1 arrest.

Keywords: Colon cancer; Sulindac sulfone; VDAC; mTORC1 pathway.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / biosynthesis
  • Anti-Inflammatory Agents, Non-Steroidal / chemistry
  • Anti-Inflammatory Agents, Non-Steroidal / metabolism
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / metabolism
  • Antineoplastic Agents / pharmacology*
  • Cell Cycle Checkpoints
  • Colonic Neoplasms / metabolism*
  • Colonic Neoplasms / pathology
  • HT29 Cells
  • Humans
  • Mechanistic Target of Rapamycin Complex 1 / antagonists & inhibitors*
  • Sulindac / analogs & derivatives*
  • Sulindac / chemistry
  • Sulindac / metabolism
  • Sulindac / pharmacology
  • Voltage-Dependent Anion Channel 1 / antagonists & inhibitors*
  • Voltage-Dependent Anion Channel 1 / metabolism
  • Voltage-Dependent Anion Channel 2 / antagonists & inhibitors*
  • Voltage-Dependent Anion Channel 2 / metabolism


  • Anti-Inflammatory Agents, Non-Steroidal
  • Antineoplastic Agents
  • VDAC1 protein, human
  • VDAC2 protein, human
  • Voltage-Dependent Anion Channel 2
  • Sulindac
  • Adenosine Triphosphate
  • Voltage-Dependent Anion Channel 1
  • Mechanistic Target of Rapamycin Complex 1
  • sulindac sulfone