Dataset Information

Interrupted Glucagon Signaling Reveals Hepatic ? Cell Axis and Role for L-Glutamine in ? Cell Proliferation.

ABSTRACT: Decreasing glucagon action lowers the blood glucose and may be useful therapeutically for diabetes. However, interrupted glucagon signaling leads to ? cell proliferation. To identify postulated hepatic-derived circulating factor(s) responsible for ? cell proliferation, we used transcriptomics/proteomics/metabolomics in three models of interrupted glucagon signaling and found that proliferation of mouse, zebrafish, and human ? cells was mTOR and FoxP transcription factor dependent. Changes in hepatic amino acid (AA) catabolism gene expression predicted the observed increase in circulating AAs. Mimicking these AA levels stimulated ? cell proliferation in a newly developed in vitro assay with L-glutamine being a critical AA. ? cell expression of the AA transporter Slc38a5 was markedly increased in mice with interrupted glucagon signaling and played a role in ? cell proliferation. These results indicate a hepatic ? islet cell axis where glucagon regulates serum AA availability and AAs, especially L-glutamine, regulate ? cell proliferation and mass via mTOR-dependent nutrient sensing.

SUBMITTER: Dean ED

PROVIDER: S-EPMC5572896 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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Publications

Interrupted Glucagon Signaling Reveals Hepatic α Cell Axis and Role for L-Glutamine in α Cell Proliferation.

Dean E Danielle ED Li Mingyu M Prasad Nripesh N Wisniewski Scott N SN Von Deylen Alison A Spaeth Jason J Maddison Lisette L Botros Anthony A Sedgeman Leslie R LR Bozadjieva Nadejda N Ilkayeva Olga O Coldren Anastasia A Poffenberger Greg G Shostak Alena A Semich Michael C MC Aamodt Kristie I KI Phillips Neil N Yan Hai H Bernal-Mizrachi Ernesto E Corbin Jackie D JD Vickers Kasey C KC Levy Shawn E SE Dai Chunhua C Newgard Christopher C Gu Wei W Stein Roland R Chen Wenbiao W Powers Alvin C AC

Cell metabolism 20170601 6

Decreasing glucagon action lowers the blood glucose and may be useful therapeutically for diabetes. However, interrupted glucagon signaling leads to α cell proliferation. To identify postulated hepatic-derived circulating factor(s) responsible for α cell proliferation, we used transcriptomics/proteomics/metabolomics in three models of interrupted glucagon signaling and found that proliferation of mouse, zebrafish, and human α cells was mTOR and FoxP transcription factor dependent. Changes in hep ...[more]

PMID: 28591638

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Project description:Energy metabolism reprogramming is becoming an increasingly important hallmark of cancer. Specifically, cancers tend to undergo metabolic reprogramming to upregulate a cell‑dependent glutamine (Gln) metabolism. Notably, hepatocellular cell adhesion molecule (HepaCAM) has been previously reported to serve a key role as a tumour suppressor. However, the possible regulatory role of HepaCAM in Gln metabolism in prostate cancer (PCa) remains poorly understood. In the present study, bioinformatics analysis predicted a significant negative correlation among the expression of HepaCAM, phosphatidylinositol‑4,5‑bisphosphate 3‑kinase catalytic subunit α (PIK3CA), glutaminase (GLS) and solute carrier family 1 member 5 (SLC1A5), components of Gln metabolism, in clinical and genomic datasets. Immunohistochemistry results verified a negative correlation between HepaCAM and PIK3CA expression in PCa tissues. Subsequently, liquid chromatography‑tandem mass spectrometry (LC‑MS/MS) and gas chromatography‑mass spectrometry (GC‑MS) assays were performed, and the results revealed markedly reduced levels of Gln and metabolic flux in the blood samples of patients with PCa and in PCa cells. Mechanistically, overexpression of HepaCAM inhibited Gln metabolism and proliferation by regulating PIK3CA in PCa cells. In addition, Gln metabolism was discovered to be stress‑resistant in PCa cells, since the expression levels of GLS and SLC1A5 remained high for a period of time after Gln starvation. However, overexpression of HepaCAM reversed this resistance to some extent. Additionally, alpelisib, a specific inhibitor of PIK3CA, effectively potentiated the inhibitory effects of HepaCAM overexpression on Gln metabolism and cell proliferation through mass spectrometry and CCK‑8 experiments. In addition, the inhibitory effect of PIK3CA on the growth of tumor tissue in nude mice was also confirmed by immunohistochemistry in vivo. To conclude, the results from the present study revealed an abnormal Gln metabolic profile in the blood samples of patients with PCa, suggesting that it can be applied as a clinical diagnostic tool for PCa. Additionally, a key role of the HepaCAM/PIK3CA axis in regulating Gln metabolism, cell proliferation and tumour growth was identified. The combination of alpelisib treatment with the upregulation of HepaCAM expression may serve as a novel method for treating patients with PCa.

Dataset Information

Interrupted Glucagon Signaling Reveals Hepatic ? Cell Axis and Role for L-Glutamine in ? Cell Proliferation.

Publications

Interrupted Glucagon Signaling Reveals Hepatic α Cell Axis and Role for L-Glutamine in α Cell Proliferation.

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