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

Publication date: 6 March 2018
Source:Cell Reports, Volume 22, Issue 10
Author(s): ZunGuo Du, XiuJuan Liu, Tao Chen, WenChao Gao, ZhengMing Wu, ZhiQian Hu, Dong Wei, ChunFang Gao, QingQuan Li
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.

Graphical abstract

Teaser

Du et al. show that a Sirt5+ subpopulation represents a critical driving force behind the development of multidrug resistance in wild-type Kras colorectal carcinomas and that Sirt5-mediated SDHA inactivation has implications for this process.


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