SSRP1/SLC3A2 Axis in Arginine Transport: A New Target for Overcoming Immune Evasion and Tumor Progression in Peripheral T-Cell Lymphoma.

in Advanced science (Weinheim, Baden-Wurttemberg, Germany) by Yimin Ren, Lei Fan, Ling Wang, Yanping Liu, Jie Zhang, Boya Wang, Ruize Chen, Xiao Chen, Lingyu Zhuang, Yaping Zhang, Handong Sun, Jianyong Li, Wenyu Shi, Hui Jin

TLDR

  • Quinacrine, a metabolic inhibitor drug, exhibits excellent antitumor activity in PTCL by downregulating intracellular arginine levels, which is essential for tumor growth and progression.
  • High SLC3A2 expression predicts poor outcomes in PTCL, and targeting SLC3A2-mediated arginine uptake could be a promising therapeutic approach.
  • Combining quinacrine with histone deacetylase inhibitors is a potential therapeutic strategy for PTCL, which warrants further investigation.

Abstract

Peripheral T-cell lymphoma (PTCL) is a heterogeneous group of mature T-cell malignancies with poor prognosis. Therefore, improved therapies are urgently required to improve patient outcomes. In this study, metabolic inhibitor drug screening reveals that quinacrine elicits excellent antitumor activity both in vitro and in vivo by downregulating intracellular arginine levels in PTCL. Single-cell transcriptomic analyses reveal aberrant arginine metabolism in patients with PTCL, characterized by excessive solute carrier family 3 member 2 (SLC3A2) mediated arginine uptake preferentially in tumor cells. High SLC3A2 expression predicts poor outcomes in PTCL, as SLC3A2-mediated arginine uptake promotes the malignant behaviors of tumor cells and induces tumor immune escape, thereby fueling tumor progression. Mechanistically, high arginine levels induce global metabolic changes, including enhanced oxidative phosphorylation by promoting nascent RNA synthesis. This work identifies structure-specific recognition protein 1 (SSRP1), which upregulates SLC3A2, as a co-transcription factor with JUNB. Quinacrine disrupts SLC3A2-mediated arginine transport by targeting SSRP1. Combining quinacrine with histone deacetylase inhibitors is a promising therapeutic strategy for PTCL.

Overview

  • Study focused on finding improved therapies for peripheral T-cell lymphoma (PTCL), a heterogeneous and poorly prognosis group of mature T-cell malignancies.
  • Metabolic inhibitor drug screening revealed quinacrine as a promising antitumor agent that downregulates intracellular arginine levels in PTCL, both in vitro and in vivo.
  • The study aimed to identify key molecular targets and develop a potential therapeutic strategy for PTCL, a cancer with poor prognosis and limited treatment options.

Comparative Analysis & Findings

  • Single-cell transcriptomic analyses revealed aberrant arginine metabolism in patients with PTCL, characterized by excessive SLC3A2-mediated arginine uptake in tumor cells.
  • High SLC3A2 expression was found to predict poor outcomes in PTCL, as it promotes malignant behaviors and tumor immune escape, thereby fueling tumor progression.
  • Quinacrine disrupted SLC3A2-mediated arginine transport by targeting SSRP1, a co-transcription factor with JUNB, highlighting the potential of combining quinacrine with histone deacetylase inhibitors as a therapeutic strategy for PTCL.

Implications and Future Directions

  • The study's findings suggest that targeting SLC3A2-mediated arginine uptake could be a promising therapeutic approach for PTCL, which is urgently needed due to the cancer's poor prognosis and limited treatment options.
  • Future studies could investigate the optimal dosing and combination regimens of quinacrine and histone deacetylase inhibitors, as well as exploring the potential role of SSRP1 as a biomarker for PTCL.
  • The study's findings also emphasize the importance of understanding the metabolic alterations underlying cancer, which could lead to the development of new therapeutic strategies and improved patient outcomes in PTCL and other cancers.
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