Targeting a Sirt5-Positive Subpopulation Overcomes Multidrug Resistance in Wild-Type Kras Colorectal Carcinomas

Cell Rep. 2018 Mar 6;22(10):2677-2689. doi: 10.1016/j.celrep.2018.02.037.

Abstract

A major obstacle for successful management of patients with colorectal carcinoma (CRC) is resistance to anti-cancer cytotoxic treatments. Here, we identified a mechanism of multidrug resistance in wild-type Kras CRCs based on the survival of a cell subpopulation characterized by Sirt5 expression. Sirt5+ cells in wild-type Kras CRCs are resistant to either chemotherapeutic agents or cetuximab and serve as a reservoir for recurrence. Sirt5 demalonylates and inactivates succinate dehydrogenase complex subunit A (SDHA), leading to an accumulation of the oncometabolite succinate. Succinate binds to and activates a reactive oxygen species-scavenging enzyme, thioredoxin reductase 2 (TrxR2), to confer chemotherapy resistance. In contrast, Sirt5+ cells exhibit an elevated succinate-to-aKG ratio that inhibits aKG-dependent dioxygenases to maintain cetuximab resistance. Our findings suggest that Sirt5 inhibitors in combination with chemotherapeutic agents and/or cetuximab may represent a therapeutic strategy for CRC patients harboring wild-type Kras.

Keywords: SDHA; Sirt5; colorectal carcinomas; drug resistance; wild-type Kras.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Cetuximab / pharmacology
  • Colorectal Neoplasms / metabolism*
  • Colorectal Neoplasms / pathology
  • DNA Demethylation / drug effects
  • Drug Resistance, Multiple* / drug effects
  • Drug Resistance, Neoplasm* / drug effects
  • Electron Transport Complex II / metabolism
  • Female
  • Histones / metabolism
  • Humans
  • Ketoglutaric Acids / metabolism
  • Mice, Inbred BALB C
  • Mice, Nude
  • Neoplasm Recurrence, Local / pathology
  • Proto-Oncogene Proteins p21(ras) / metabolism*
  • Sirtuins / metabolism*
  • Succinates / metabolism
  • Thioredoxin Reductase 2 / metabolism

Substances

  • Histones
  • KRAS protein, human
  • Ketoglutaric Acids
  • Succinates
  • Electron Transport Complex II
  • SDHA protein, human
  • TXNRD2 protein, human
  • Thioredoxin Reductase 2
  • SIRT5 protein, human
  • Sirtuins
  • Proto-Oncogene Proteins p21(ras)
  • Cetuximab