Asparagine synthetase and G-protein coupled estrogen receptor are critical responders to nutrient supply in KRAS mutant colorectal cancer

Authors

Lingeng Lu, Department of Chronic Disease Epidemiology, Yale School of Public Health, Yale University, New Haven, Connecticut, USA.Follow
Qian Zhang, Department of Environmental Health Sciences, Yale School of Public Health, Yale University, New Haven, Connecticut, USA.Follow
Oladimeji Aladelokun, Department of Environmental Health Sciences, Yale School of Public Health, Yale University, New Haven, Connecticut, USA.Follow
Domenica Berardi, Department of Environmental Health Sciences, Yale School of Public Health, Yale University, New Haven, Connecticut, USA.Follow
Xinyi Shen, Department of Environmental Health Sciences, Yale School of Public Health, Yale University, New Haven, Connecticut, USA.Follow
Audrey Marin, Department of Environmental Health Sciences, Yale School of Public Health, Yale University, New Haven, Connecticut, USA.
Rolando Garcia-Milian, Department of Environmental Health Sciences, Yale School of Public Health, Yale University, New Haven, Connecticut, USA.Follow
Jatin Roper, Division of Gastroenterology, Department of Medicine, Duke University, Durham, North Carolina, USA.Follow
Sajid A. Khan, Section of Surgical Oncology, Department of Surgery, Yale School of Medicine, Yale Cancer Center, Yale University, New Haven, Connecticut, USA.Follow
Caroline H. Johnson, Department of Environmental Health Sciences, Yale School of Public Health, Yale University, New Haven, Connecticut, USA.Follow

Document Type

Article

Publication Title

International journal of cancer

Abstract

Survival differences exist in colorectal cancer (CRC) patients by sex and disease stage. However, the potential molecular mechanism(s) are not well understood. Here we show that asparagine synthetase (ASNS) and G protein-coupled estrogen receptor-1 (GPER1) are critical sensors of nutrient depletion and linked to poorer outcomes for females with CRC. Using a 3D spheroid model of isogenic SW48 KRAS wild-type (WT) and G12A mutant (MT) cells grown under a restricted nutrient supply, we found that glutamine depletion inhibited cell growth in both cell lines, whereas ASNS and GPER1 expression were upregulated in KRAS MT versus WT. Estradiol decreased growth in KRAS WT but had no effect on MT cells. Selective GPER1 and ASNS inhibitors suppressed cell proliferation with increased caspase-3 activity of MT cells under glutamine depletion condition particularly in the presence of estradiol. In a clinical colon cancer cohort from The Cancer Genome Atlas, both high GPER1 and ASNS expression were associated with poorer overall survival for females only in advanced stage tumors. These results suggest KRAS MT cells have mechanisms in place that respond to decreased nutrient supply, typically observed in advanced tumors, by increasing the expression of ASNS and GPER1 to drive cell growth. Furthermore, KRAS MT cells are resistant to the protective effects of estradiol under nutrient deplete conditions. The findings indicate that GPER1 and ASNS expression, along with the interaction between nutrient supply and KRAS mutations shed additional light on the mechanisms underlying sex differences in metabolism and growth in CRC, and have clinical implications in the precision management of KRAS mutant CRC.

First Page

52

Last Page

68

DOI

10.1002/ijc.35104

Publication Date

1-1-2025

Recommended Citation

Lu, Lingeng; Zhang, Qian; Aladelokun, Oladimeji; Berardi, Domenica; Shen, Xinyi; Marin, Audrey; Garcia-Milian, Rolando; Roper, Jatin; Khan, Sajid A.; and Johnson, Caroline H., "Asparagine synthetase and G-protein coupled estrogen receptor are critical responders to nutrient supply in KRAS mutant colorectal cancer" (2025). Surgery. 183.
https://scholar.bridgeporthospital.org/surgery/183

Identifier

39039782 (pubmed); NIHMS2008499 (mid); PMC11537827 (pmc); 10.1002/ijc.35104 (doi)