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 wildtype 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.
[1]Fudan Univ, Sch Basic Med Sci, Dept Pathol, Shanghai 200032, Peoples R China.
[2]Fudan Univ, HuaShan Hosp, Dept Pathol, Shanghai 200040, Peoples R China.
[3]Fudan Univ, ZhongShan Hosp, Endoscopy Ctr, Shanghai 200032, Peoples R China.
[4]Second Mil Med Univ, ChangZheng Hosp, Dept Gen Surg, Shanghai 200003, Peoples R China.
[5]PLA Cent Hosp 150, Dept Anus & Intestine Surg, Luoyang 471003, Henan, Peoples R China.
(8.0+极速模式)