Aspartate Transporter SLC1A3 Promotes Colorectal Cancer via MDM2-p53 Pathway and M2 Macrophage Polarization

Sep 23, 2026

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Colorectal cancer (CRC) is a leading global digestive-system malignancy, and metabolic reprogramming is a key hallmark of cancer. Aspartate is a proteinogenic non-essential amino acid that supports cancer-cell functions, and SLC1A3 is the main aspartate transporter, though its CRC role was unclear. SLC1A3 is markedly upregulated in CRC tissues, correlating with poor prognosis. Mechanistically, SLC1A3 activates the DAG/PKC/MDM2 signaling axis to promote CRC proliferation, invasion, and migration in cells and organoids, while inducing an immunosuppressive M2 macrophage phenotype via IL17c and CSF2 upregulation. These findings indicate a dual role for SLC1A3 in CRC progression and suggest therapeutic targeting potential.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages15

Reading Time38 min

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Introduction

CRC burden and treatment background

Metabolic reprogramming and aspartate biology

SLC1A3 transporter functions and links to cancer metabolism

Cancer Science ORIGINAL ARTICLE OPEN ACCESS Carcinogenesis Aspartate Transporter SLC1A3 Promotes Colorectal Cancer via MDM2-p53 Pathway and M2 Macrophage Polarization Chao Deng1,2 | You Zhou2 | Sijie Song2 | Hongtao Liu2 | Siqi Liao2 | Li Zhou2 | Siyuan Chen2 | Zhihang Zhou2 | Song He2 | Bingrong Liu1 1Department of Gastroenterology and Hepatology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China | 2Department of Gastroenterology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China Correspondence: Song He ([hedoctor65@cqmu.edu.cn](hedoctor65@cqmu.edu.cn)) | Bingrong Liu ([fccliubr@zzu.edu.cn](fccliubr@zzu.edu.cn)) Received: 26 August 2025 | Revised: 5 April 2026 | Accepted: 9 April 2026 Keywords: aspartate | colorectal cancer | macrophage polarization | p53 | SLC1A3 ABSTRACT Colorectal cancer (CRC) remains the most prevalent malignancy of the digestive system globally and ranks second in cancerrelated deaths worldwide. Metabolic reprogramming is one of the hallmarks of cancer. Aspartate is a proteinogenic non-essential amino acid with several essential functions in cancer cells. SLC1A3 is the main aspartate transporter, but its role in CRC needs to be elucidated. We found that SLC1A3 is significantly overexpressed in CRC tissues compared to adjacent normal tissues, and elevated SLC1A3 expression is associated with poor prognosis. Further, SLC1A3 could enhance the proliferation, invasion, migration of CRC cells and organoids by activating the DAG/PKC/MDM2 signaling axis. In addition, we revealed that SLC1A3 in CRC cells could induce the immunosuppressive M2 phenotype of macrophages via upregulating IL17c and CSF2 . In sum, these findings suggest that SLC1A3 plays a dual role in CRC progression and may represent a promising target for therapeutic intervention. 1 | Introduction Colorectal cancer (CRC) remains the most prevalent malignancy of the digestive system globally and ranks second in cancer-related deaths worldwide [1, 2] . According to the latest data from the National Central Cancer Registry of China (NCCR), approximately 517,100 new CRC cases andover 240,000 CRC-related deaths were recorded in China in 2022 [3] Similarly, in the United States, the American Cancer Society (ACS) projects about 152,810 new CRC cases in 2024, with an estimated 53,010 deaths, reflecting a slight increase compared to the previous year [4] . Notably, the incidence of CRC is alarmingly increasing among younger populations, making it the leading cause of cancer death among men under 50 and the second-leading cause among women in the same age group [5, 6] . Metastasis is the main cause of CRC-related death [7] About 25% CRC patients have distant metastasis atthe initial diagnosis, and about half of the patients develop distant metastasis during the course of disease. Currently, treatment strategies for CRC involve multimodal approaches including surgical intervention, chemotherapy, radiotherapy, and targeted therapies tailored to the tumor's stage and molecular characteristics [8] . Common chemotherapy regimens, such as FOLFOX (5-fluorouracil, leucovorin, and oxaliplatin) and CAPOX (capecitabine and oxaliplatin), have shown efficacy in both adjuvant and metastatic settings. Nevertheless, | Abbreviations: ACS, American Cancer Society; Asp, aspartate; ATCC, American Type Culture Collection; CAPOX, capecitabine and oxaliplatin; COAD, Colon Adenocarcinoma; CRC, colorectal cancer; CSF2, colony-stimulating factor 2; DAG, diacylglycerol; DEGs, differentially expressed genes; DFS, disease-free survival; FBS, fetal bovine serum; FOLFOX, 5-fluorouracil leucovorin and oxaliplatin; GOT, glutamate oxalacetate transaminases; IHC, immunohistochemistry; IL17C, interleukin 17C; NCCR, National Central Cancer Registry of China; OE, overexpression; OS, overall survival; READ, Rectum Adenocarcinoma; SLC1A3, solute carrier family 1 member 3; SPF, specific pathogen-free; STR, short t

FAQs

What is the main focus of this study on colorectal cancer?

The study investigates how the aspartate transporter SLC1A3 drives colorectal cancer progression through signaling pathways and effects on immune cells.

How does SLC1A3 influence CRC cell behavior?

SLC1A3 enhances CRC cell proliferation, invasion, and migration by activating the DAG/PKC/MDM2 signaling axis in cells and organoids.

What role does SLC1A3 play in macrophage polarization?

In CRC, SLC1A3 promotes an immunosuppressive M2 macrophage phenotype by upregulating IL17c and CSF2.

Sep 23, 2026

Uploaded by Aldword