HepaCAM‑PIK3CA axis regulates the reprogramming of glutamine metabolism to inhibit prostate cancer cell proliferation

He,Zhenting; Gao,Yingying; Li,Ting; Yu,Chaowen; Ou,Liping; Luo,Chunli

doi:10.3892/ijo.2022.5327

HepaCAM‑PIK3CA axis regulates the reprogramming of glutamine metabolism to inhibit prostate cancer cell proliferation

Authors:
- Zhenting He
- Yingying Gao
- Ting Li
- Chaowen Yu
- Liping Ou
- Chunli Luo
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Affiliations: Key Laboratory of Clinical Laboratory Diagnostics (Ministry of Education), School of Laboratory Medicine, Chongqing Medical University, Chongqing 400016, P.R. China, Department of Laboratory Diagnosis, People's Hospital of Chongqing Banan District, Chongqing 401320, P.R. China, Center for Clinical Molecular Medicine, Children's Hospital of Chongqing Medical University, Chongqing 400014, P.R. China
Published online on: February 22, 2022 https://doi.org/10.3892/ijo.2022.5327
Article Number: 37
Copyright: © He et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

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.

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