Nrf2 Activation Sensitizes K-Ras Mutant Pancreatic Cancer Cells to Glutaminase Inhibition

Abstract

Pancreatic cancer remains intractable owing to the lack of effective therapy for unresectable cases. Activating mutations of K-ras are frequently found in pancreatic cancers, but these have not yet been targeted by cancer therapies. The Keap1-Nrf2 system plays a crucial role in mediating the oxidative stress response, which also contributes to cancer progression. Nrf2 activation reprograms the metabolic profile to promote the proliferation of cancer cells. A recent report suggested that K-ras- and Nrf2-active lung cancer cells are sensitive to glutamine depletion. This finding led to the recognition of glutaminase inhibitors as novel anticancer agents. In the current study, we used murine pancreatic cancer tissues driven by mutant K-ras and p53 to establish cell lines expressing constitutively activated Nrf2. Genetic or pharmacological Nrf2 activation in cells via Keap1 deletion or Nrf2 activation sensitized cells to glutaminase inhibition. This phenomenon was confirmed to be dependent on K-ras activation in human pancreatic cancer cell lines harboring mutant K-ras, i.e., Panc-1 and MiaPaCa-2 in response to DEM pretreatment. This phenomenon was not observed in BxPC3 cells harboring wildtype K-ras. These results indicate the possibility of employing Nrf2 activation and glutaminase inhibition as novel therapeutic interventions for K-ras mutant pancreatic cancers.

HIF-1 and NRF2; Key Molecules for Malignant Phenotypes of Pancreatic Cancer

“…Dependence to stress response mechanisms in cancer cells or PSCs could be an ideal target for this therapy concept. Sensitization to glutaminase inhibition by NRF2 activation is a good example [ 105 ]. Dissection of these complex mechanisms is essential for the development of effective therapies for pancreatic cancer.…”

“…Because pancreatic cancer cells frequently harbor mutant K-ras , a recent study assessed the relationship between NRF2 activation and CB-839 sensitivity in pancreatic cancer. Established murine pancreatic cancer cell lines from Keap1-null , Nrf2 +/− KPC mouse pancreatic cancer cells showed increased nuclear accumulation of Nrf2 [ 105 ]. These cell lines were more sensitive to CB-839 treatment than Keap1-null and Nrf2-null KPC mouse pancreatic cancer cell lines.…”

Stress Granules Involved in Formation, Progression and Metastasis of Cancer: A Scoping Review

“…The effect on this interaction inhibits translation and leads to the formation of SGs (Kim et al, 2007). Instead, mutant KRAS with up-regulation of the nuclear factor erythroid 2-related factor 2 (NRF2) causes rearrangement of glutamine metabolic pathways in tumor cells (Hamada et al, 2021). In addition to its effect on glutamine metabolic pathways, NRF2 is involved in the 15d-PGJ2 effect on the SGs formation (Mukhopadhyay et al, 2020).…”

Role of Nrf2 in Pancreatic Cancer

“…KPCN-derived cell lines revealed increased sensitivity to oxidative stress and chemotherapeutic agent. Interestingly, the simultaneous activation of Kras and Nrf2 by Kras mutation and Keap1 deletion, respectively, did not promote pancreatic cancer development but led to pancreatic atrophy [ 73 ].…”