The NRF2-driven antioxidant program shields translation-related proteins to drive PDAC maintenance.

  • Major finding: The NRF2-driven antioxidant program shields translation-related proteins to drive PDAC maintenance.

  • Mechanism: NRF2 inhibits oxidation of translational regulatory factors and drives autocrine EGFR signaling.

  • Impact: Combined inhibition of AKT and glutathione synthesis may be a potential therapy for PDAC.

Oncogenic KRAS and loss of TP53 are two of the most frequent genetic alterations that drive pancreatic ductal adenocarcinoma (PDAC). Having recently shown that mutant KRAS expression upregulates the transcription factor nuclear factor, erythroid 2 like 2 (NRF2, encoded by NFE2L2)–driven transactivation of antioxidant-regulated genes to drive PDAC initiation, Chio and colleagues further characterized the role of NRF2 in PDAC tumorigenesis. NRF2/NFE2L2 expression was elevated in patient PDAC-derived (hT) organoids, and NRF2 ablation resulted in organoid death or highly elevated reactive oxygen species (ROS) levels and decreased proliferation. Similarly, engraftment of mutant Kras (K) organoids derived from the pancreata of NFE2L2-deficient mice was decreased compared to K organoids derived from wild-type NFE2L2 mice. NRF2-deficient K and mutant Kras/Trp53R172H/+ (KP) organoids exhibited decreased glutathione (GSH) and increased ROS compared to NRF2-proficient counterparts. Analysis of the cysteine proteome in KP organoids showed that NRF2 deficiency resulted in elevated cysteine oxidation of translation-related proteins, including regulators of translation. Consistent with these findings, hT, K, and KP organoids deficient of NRF2 all exhibited decreased cap-dependent mRNA translation of prosurvival proteins and reduced autocrine EGFR activation, which is critical for promoting the initiation of cap-dependent mRNA translation. In vitro, treatment of hT and KP organoids with the pan-AKT inhibitor MK2206 resulted in decreased protein synthesis and inhibition of translation initiation, the effect of which was further augmented through combined treatment with the GSH synthesis inhibitor buthionine sulfoximine (BSO). Similarly, combination treatment with BSO and MK2206 was significantly more efficacious than single-drug treatment in inhibiting growth of a PDAC xenograft and a genetically engineered mouse model of PDAC. Together, these findings elucidate a mechanism by which antioxidants promote PDAC tumorigenesis and suggest that combined targeting of GSH synthesis and AKT may be a potential therapy for patients with PDAC.

Chio II, Jafarnejad SM, Ponz-Sarvise M, Park Y, Rivera K, Palm W, et al. NRF2 promotes tumor maintenance by modulating mRNA translation in pancreatic cancer. Cell 2016 Jul 28 [Epub ahead of print].

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