Glutamine utilization in cancer cells

Shuo Qie

doi:10.17918/00009450

Metabolic transformation forms the biochemical foundation for oncogenic transformation. In addition to being utilized for protein translation, glutamine (Gln) can serve as carbon and nitrogen sources to fulfill energetic and biosynthetic needs for proliferating cells. However, during progression, solid tumors frequently develop an ischemic condition, resulting in low Gln levels. A better understanding of tumor cells' adaptive strategy to Gln-deprivation may provide new therapeutic targets. Being the first and rate limiting step for Gln utilization, glutaminolysis is catalyzed by glutaminase (GLS). It has been hypothesized that oncogenes may coordinate glutaminolysis with cell proliferation. In Chapter 2, we used breast cancer cells as a model and studied whether ErbB2 signaling regulates Gln utilization in breast cancer cells. Our results indicate that ErbB2 activation enhances GLS1 expression, and NF-[kappa]B signaling pathway mediates this regulation. Furthermore, we identified the enhanced GLS1 expression promotes cell proliferation of ErbB2-positive breast cancer cells. In Chapter 3, we studied the global gene expression reprogramming of tumor cells upon Gln-deprivation using cDNA microarray combined with ingenuity pathway analysis. Our data show that acute Gln-deprivation leads to G 2/M cell cycle arrest and eventually apoptosis. In comparison, the adapted MM01 cells show a slow growing phenotype and a distinctive profile of gene expression reprogramming, including ATF4 activation and the upregulation of stress responsive genes, such as Stanniocalcin 2 (STC2). In Chapters 4 and 5, we studied the role of STC2 in tumor cells' adaptation to Gln-deprivation. Our data show that STC2 upregulation switches tumor cells' priority from proliferation to survival upon Gln-deprivation. The activation of eIF2[alpha]-ATF4 pathway is implicated in STC2 upregulation upon Gln-deprivation. STC2 promoter region possesses ATF4 binding site, and ATF4 directly interacts with this site. Neither secretion nor stability of STC2 is affected by Gln-deprivation. Finally, our data show inhibition of GLS activity is sufficient to trigger eIF2[alpha]-ATF4 activation and STC2 upregulation, indicating lack of Gln utilization, not Gln itself, triggers the eIF2[alpha]-ATF4-STC2 pathway, which switches cells' priority from proliferation to survival. Taken together, our data indicate that Gln utilization and adaptive mechanisms to Gln-deprivation can be explored as novel therapeutic targets for cancer treatment.

Glutamine utilization in cancer cells

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Glutamine utilization in cancer cells

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