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

ZunGuo Du1, XiuJuan Liu2, Tao Chen3

  • 1Department of Pathology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China; Department of Pathology, HuaShan Hospital, Fudan University, Shanghai 200040, China.

Cell Reports
|March 8, 2018
PubMed

Insights

A novel mechanism of multidrug resistance in colorectal cancer (CRC) involves Sirt5-expressing cells. These cells, fueled by succinate accumulation, resist chemotherapy and cetuximab, potentially driving recurrence.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Multidrug resistance (MDR) is a significant challenge in colorectal cancer (CRC) management.
  • A subpopulation of cells expressing Sirt5 contributes to treatment resistance in wild-type Kras CRC.
  • These Sirt5-expressing cells act as a reservoir for cancer recurrence.

Purpose of the Study:

  • To elucidate the mechanism of multidrug resistance mediated by Sirt5 in wild-type Kras colorectal carcinoma.
  • To identify the metabolic pathways and molecular interactions involved in Sirt5-driven resistance.
  • To explore potential therapeutic strategies targeting Sirt5 for CRC treatment.

Main Methods:

  • Analysis of Sirt5 expression in wild-type Kras CRC patient samples.
  • Investigating the enzymatic activity of Sirt5, including its interaction with succinate dehydrogenase complex subunit A (SDHA).
  • Assessing the role of succinate accumulation and its downstream effects on reactive oxygen species (ROS) scavenging and enzyme activity.

Main Results:

  • Sirt5 demalonylates and inactivates SDHA, leading to succinate accumulation.
  • Accumulated succinate activates thioredoxin reductase 2 (TrxR2), conferring resistance to chemotherapeutic agents.
  • Sirt5+ cells exhibit an elevated succinate-to-alpha-ketoglutarate (aKG) ratio, inhibiting aKG-dependent dioxygenases and conferring cetuximab resistance.

Conclusions:

  • Sirt5-expressing cells are a key driver of resistance to chemotherapy and cetuximab in wild-type Kras CRC.
  • The identified Sirt5-mediated metabolic reprogramming provides a survival advantage to cancer cells.
  • Targeting Sirt5 in combination with standard therapies may offer a novel therapeutic approach for CRC patients with wild-type Kras.
Keywords:
SDHASirt5colorectal carcinomasdrug resistancewild-type Kras

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