Abstract
Aspirin is one of the most promising over-the-counter drugs to repurpose for cancer treatment. In particular, aspirin has been reported to be effective against PIK3CA-mutated colorectal cancer (CRC); however, little information is available on how the PIK3CA gene status affects its efficacy. We found that the growth inhibitory effects of aspirin were impaired upon glutamine deprivation in PIK3CA-mutated CRC cells. Notably, glutamine dependency of aspirin-mediated growth inhibition was observed in PIK3CA-mutated cells but not PIK3CA wild type cells. Mechanistically, aspirin induced G1 arrest in PIK3CA-mutated CRC cells and inhibited the mTOR pathway, inducing the same phenotypes as glutamine deprivation. Moreover, our study including bioinformatic approaches revealed that aspirin increased the expression levels of glutaminolysis-related genes with upregulation of activating transcription factor 4 (ATF4) in PIK3CA-mutated CRC cells. Lastly, the agents targeting glutaminolysis demonstrated significant combined effects with aspirin on PIK3CA-mutated CRC cells. Thus, these findings not only suggest the correlation among aspirin efficacy, PIK3CA mutation and glutamine metabolism, but also the rational combinatorial treatments of aspirin with glutaminolysis-targeting agents against PIK3CA-mutated CRC.
Highlights
Non-steroidal anti-inflammatory drugs (NSAIDs) have held great promise as a repurposed drug for the prevention and treatment of cancer, especially colorectal cancer (CRC) [1,2]
Whereas the growth of PIK3CA-mutated cancer including CRC is dependent on glucose metabolism [13], recent reports demonstrated that PIK3CA mutations in CRC confer the dependency on glutamine metabolism [14], which may be targetable to suppress the growth of PIK3CA-mutated CRC [15]
HCT116 cells harboring PIK3CA mutations accelerated cell growth in a glutamine dose-dependent manner (Figure 1a,b), whereas PIK3CA wild type human CRC SW480 cells were not affected by glutamine supplementation (Figure 1c)
Summary
Non-steroidal anti-inflammatory drugs (NSAIDs) have held great promise as a repurposed drug for the prevention and treatment of cancer, especially colorectal cancer (CRC) [1,2]. As for the treatment for CRC, a recent study suggested that regular use of aspirin after CRC diagnosis can prolong the survival of patients with PIK3CA active mutations [5], and this was confirmed by other large cohort. PIK3CA mutations in two hot spots in both exons 9 and 20 may be associated with a poorer prognosis [9,10]. As another example, PIK3CA mutations negatively impact the response of CRC to first-line chemotherapies, including FOLFOX, XELOX and FOLFIRI [11] and anti-EGFR-targeted therapies [12]. Whereas the growth of PIK3CA-mutated cancer including CRC is dependent on glucose metabolism [13], recent reports demonstrated that PIK3CA mutations in CRC confer the dependency on glutamine metabolism [14], which may be targetable to suppress the growth of PIK3CA-mutated CRC [15]
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