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.
Highlights
Accepted: 11 February 2021The prognosis of pancreatic cancer remains dismal despite improved diagnostic methods
Conformational changes in Keap1 induced by cellular reactive oxygen species and electrophiles result in the nuclear accumulation of Nrf2, a transcription factor that induces the expression of cytoprotective genes [6]
Panc-1 and MiaPaCa-2 cells with CB-839 in the background of diethyl malate of (DEM) treatment resulted in in reduced cell viability(Figure (Figure5B); 5B);,this thisphenomenon phenomenon was was not not observed reduced cell viability observed in in BxPC3. These results indicated that the glutaminase inhibitor
Summary
Accepted: 11 February 2021The prognosis of pancreatic cancer remains dismal despite improved diagnostic methods. The main reason for this is the lack of effective therapies for advanced pancreatic cancer. Targeted therapies for driver mutations in several types of malignancies such as gastrointestinal stromal tumor and non-small-cell lung cancer with KIT mutation and ALK translocation, respectively, have led to better prognosis [1,2]. More than 90% of the pancreatic cancers harbor activating K-ras mutations [3], but these mutations have not yet been successfully targeted. The molecules downstream of K-ras signaling are recognized as alternative targets, such as mitogen-activated protein/extracellular signal-regulated kinase kinase and [4] and protein kinase C [5]. The deletion of Nrf in mouse models with mutant K-ras-driven pancreatic cancer resulted in reduced formation of pancreatic lesions [7,8].
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