Scholarlink

Background <p>Cancer cells depend heavily on phosphate and its main exporter, XPR1. Therefore, phosphate homeostasis may represent an actionable vulnerability for several indications. In this study, we investigated the molecular mechanisms by which ovarian cell lines are dependent on XPR1 function. We further investigated whether this vulnerability is conserved in lung cancer models, potentially revealing a novel therapeutic target across multiple cancer types.</p> Methods <p>The functional role of XPR1 was confirmed in a panel of ovarian cell lines. We then broadened the scope of our research by examining lung cancer cell lines that exhibited dysregulated phosphate transporter expression. The mechanistic role of XPR1 was validated through complementary approaches: targeted gene silencing and pharmacological inhibition using an XPR1-specific neutralizing ligand.</p> Results <p>We demonstrated that PAX8-dependent overexpression of the phosphate transporter SLC34A2 in ovarian cancer (OV) cell lines was associated with impaired phosphate metabolism, and made tumor cells vulnerable to inhibition of XPR1 by gene silencing or a neutralizing ligand (XRBD). Moreover, in vivo conditional knockdown experiments demonstrated that XPR1 gene silencing inhibited tumor growth of an OV cell line-derived xenograft model, and confirmed this synthetic lethal phenotype.</p> <p>To further document the indications that may display susceptibilities towards unbalanced phosphate metabolism, we reviewed public datasets of human cancer. This investigation highlighted frequent genomic or epigenetic alterations of genes encoding several phosphate transporters (including SLC20A1/2 or SLC34A2) in lung and uterine tumors. These observations suggested a vulnerability to XPR1 inhibition. Using in vitro cell models, we demonstrated that genetic silencing of XPR1 or treatment with XRBD impairs cell growth, leading to toxic intracellular phosphate accumulation and cell death in lung cancer cells, characterized by high baseline phosphate import via SLC20A1/2 or SLC34A2 transporters.</p> Conclusion <p>Our study highlighted a potential therapeutic vulnerability associated with the dysregulation of phosphate homeostasis in ovarian and lung cancers, suggesting XPR1 as a potential target in these indications.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

XPR1, key regulator of phosphate homeostasis and potential drug target for ovarian and lung cancer

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年7月29日

查看全文
  • Pascal Pannier,
  • Amel Lebsir,
  • Vincent Ogor,
  • Elycia Calvet,
  • Elodie Chastel,
  • Stéphane D’Agostino,
  • Loreley Calvet,
  • Sukhvinder Sidhu,
  • Anand Kumar,
  • Alexey Rak,
  • Emilia Puig Lombardi,
  • Christophe Marcireau,
  • Isabelle Meaux,
  • Christophe Henry

摘要

Background

Cancer cells depend heavily on phosphate and its main exporter, XPR1. Therefore, phosphate homeostasis may represent an actionable vulnerability for several indications. In this study, we investigated the molecular mechanisms by which ovarian cell lines are dependent on XPR1 function. We further investigated whether this vulnerability is conserved in lung cancer models, potentially revealing a novel therapeutic target across multiple cancer types.

Methods

The functional role of XPR1 was confirmed in a panel of ovarian cell lines. We then broadened the scope of our research by examining lung cancer cell lines that exhibited dysregulated phosphate transporter expression. The mechanistic role of XPR1 was validated through complementary approaches: targeted gene silencing and pharmacological inhibition using an XPR1-specific neutralizing ligand.

Results

We demonstrated that PAX8-dependent overexpression of the phosphate transporter SLC34A2 in ovarian cancer (OV) cell lines was associated with impaired phosphate metabolism, and made tumor cells vulnerable to inhibition of XPR1 by gene silencing or a neutralizing ligand (XRBD). Moreover, in vivo conditional knockdown experiments demonstrated that XPR1 gene silencing inhibited tumor growth of an OV cell line-derived xenograft model, and confirmed this synthetic lethal phenotype.

To further document the indications that may display susceptibilities towards unbalanced phosphate metabolism, we reviewed public datasets of human cancer. This investigation highlighted frequent genomic or epigenetic alterations of genes encoding several phosphate transporters (including SLC20A1/2 or SLC34A2) in lung and uterine tumors. These observations suggested a vulnerability to XPR1 inhibition. Using in vitro cell models, we demonstrated that genetic silencing of XPR1 or treatment with XRBD impairs cell growth, leading to toxic intracellular phosphate accumulation and cell death in lung cancer cells, characterized by high baseline phosphate import via SLC20A1/2 or SLC34A2 transporters.

Conclusion

Our study highlighted a potential therapeutic vulnerability associated with the dysregulation of phosphate homeostasis in ovarian and lung cancers, suggesting XPR1 as a potential target in these indications.