Glutamate‐ammonia ligase and reduction of G0 population in PANC‐1 cells

Abstract

In our previous study, we screened and isolated genes that were up-regulated after partial pancreatectomy using transcriptomic analysis and glutamate-ammonia ligase (GLUL) was selected for further study based on its effect on differentiation and proliferation. In the immunohistochemical analysis, GLUL was highly up-regulated in the acinar cells and the ductal cells in the pancreas damaged through partial pancreatectomy. Overexpression of GLUL enhanced the proliferation of PANC-1 cells and INS-1 cells. GLUL overexpression shifted the major population of PANC-1 cells from the G0/G1 phase to G2/M phase. In the double thymidine blocking analysis, similar cycle duration was observed between mock cells and GLUL-overexpressing cells while GLUL-overexpressing cells were partially resistant to thymidine blocking. In the FACS analysis of cells stained with Pyronin Y and Hoechst 33342, GLUL-overexpressing cells showed lower population of cells in the G0-quiescent phase than mock cells (5-12%). In addition, GLUL-overexpressing cells had high activation levels of AKT, ERK1/2, JNK, PCNA, c-FOS, and P70S6K in PANC-1 cells. Taken together, these results suggest that GLUL contributes to pancreatic regeneration.

GLUL Promotes Cell Proliferation in Breast Cancer

“…This protein plays a role in ammonia and glutamate detoxification, acid-base homeostasis, cell signaling, and cell proliferation [Zhou et al, 2010]. The expression of GLUL was related to cell proliferation in the liver [Wu, 1984], intestinal epithelium [DeMarco et al, 1999], epiretinal membrane [Kase et al, 2006], and skin [Vermeulen et al, 2008;Choi et al, 2013]. GLUL was up-regulated in hepatocellular carcinoma [Christa et al, 1994;Di Tommaso et al, 2009;Long et al, 2010;Hale et al, 2016], glioblastoma [Rosati et al, 2013;Tardito et al, 2015], prostate cancer [Shi et al, 2014], and may be a novel marker for diagnosis.…”

High expression of glutamate‐ammonia ligase is associated with unfavorable prognosis in patients with ovarian cancer

“…GLUL is a crucial enzyme that regulates the conversion between glutamine and glutamate. 6 It has been widely studied in microorganisms, plants, and animals. [7][8][9][10] This protein plays a role in ammonia and glutamate detoxification, acidbase homeostasis, cell signaling, and cell proliferation.…”

“…11 The expression of GLUL was related to cell proliferation in the liver, 12 intestinal epithelium, 13 epiretinal membrane, 14 and skin. 6,15 GLUL was up-regulated in hepatocellular carcinoma, [16][17][18][19] glioblastoma, 20,21 prostate cancer, 22 breast cancer. 23 Co-targeting glutamine synthetase in stroma and glutaminase in cancer cells reduces tumor weight, nodules, and metastasis.…”

“…Glutamine is converted from glutamate and the balance of these two compounds is important to the regulation of ammonia metabolism and neuroendocrine signaling. GLUL is a crucial enzyme that regulates the conversion between glutamine and glutamate . It has been widely studied in microorganisms, plants, and animals .…”

“…This protein plays a role in ammonia and glutamate detoxification, acid‐base homeostasis, cell signaling, and cell proliferation . The expression of GLUL was related to cell proliferation in the liver, intestinal epithelium, epiretinal membrane, and skin . GLUL was up‐regulated in hepatocellular carcinoma, glioblastoma, prostate cancer, breast cancer .…”