Scholarlink

<p>Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype with limited therapeutic options. Here, we investigated how integrin-dependent signaling pathways regulate tumor metabolism and therapeutic vulnerability in TNBC. Pharmacological inhibition of the integrin/FAK axis and/or BRD4 induced cell cycle arrest, autophagy, and senescence in highly proliferative cells, consistent with a metabolic stress phenotype. Metabolomic analyses using [U-¹³C]-glucose revealed a marked suppression of glycolytic carbon flux, accompanied by an approximately 30-47% reduction in intracellular NAD⁺ levels and coordinated alterations in NADH and tricarboxylic acid (TCA) cycle intermediate α-ketoglutarate. Mechanistically, we identified nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in NAD⁺ biosynthesis, as a central metabolic node integrating signaling/function of the two axes. NAMPT expression/activity was sustained transcriptionally or post-translationally, including sirtuin-associated deacetylation and neddylation-dependent proteasomal turnover. In BRCA1/2-deficient TNBC, integrin-FAK and NAMPT/NAD<sup>+</sup> pathways converged on Wnt/β-catenin signaling to regulate DNA repair, and response to PARP1/2 inhibitors. Co-inhibiting FAK and NAMPT synergistically suppressed tumor growth by approximately 80%. Elevated stromal NAMPT expression was associated with a trend toward favorable clinical outcomes. Collectively, these findings uncover a previously unrecognized crosstalk between integrin/FAK and NAMPT/NAD⁺ pathways in TNBC and identify a synthetic lethal–like therapeutic vulnerability that warrants further evaluation in clinically relevant models.</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

Crosstalk between integrin signaling and NAD⁺ biosynthetic pathways promotes glycolysis, proliferation, survival, and tumor growth in triple-negative breast cancer

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年4月29日

查看全文
  • Orion Spellecy,
  • Javeria Qadir,
  • Han Rongbo,
  • Kai Zhu,
  • Xu Bingwei,
  • Yang Zhang,
  • Isha Aryal,
  • Ruei-Lung Lin,
  • An-Hsuan Lin,
  • Abu Saleh Mosa Faisal,
  • Dana Napier,
  • Dava Piecoro,
  • Tim Scott,
  • Penghui Lin,
  • Li Chen,
  • Lawrence D. Brewer,
  • Chi Wang,
  • Natasha Kyprianou,
  • Zhenheng Guo,
  • Ruihua Guo,
  • Olivier Thibault,
  • Burton B. Yang,
  • Xiuwei H. Yang

摘要

Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype with limited therapeutic options. Here, we investigated how integrin-dependent signaling pathways regulate tumor metabolism and therapeutic vulnerability in TNBC. Pharmacological inhibition of the integrin/FAK axis and/or BRD4 induced cell cycle arrest, autophagy, and senescence in highly proliferative cells, consistent with a metabolic stress phenotype. Metabolomic analyses using [U-¹³C]-glucose revealed a marked suppression of glycolytic carbon flux, accompanied by an approximately 30-47% reduction in intracellular NAD⁺ levels and coordinated alterations in NADH and tricarboxylic acid (TCA) cycle intermediate α-ketoglutarate. Mechanistically, we identified nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in NAD⁺ biosynthesis, as a central metabolic node integrating signaling/function of the two axes. NAMPT expression/activity was sustained transcriptionally or post-translationally, including sirtuin-associated deacetylation and neddylation-dependent proteasomal turnover. In BRCA1/2-deficient TNBC, integrin-FAK and NAMPT/NAD+ pathways converged on Wnt/β-catenin signaling to regulate DNA repair, and response to PARP1/2 inhibitors. Co-inhibiting FAK and NAMPT synergistically suppressed tumor growth by approximately 80%. Elevated stromal NAMPT expression was associated with a trend toward favorable clinical outcomes. Collectively, these findings uncover a previously unrecognized crosstalk between integrin/FAK and NAMPT/NAD⁺ pathways in TNBC and identify a synthetic lethal–like therapeutic vulnerability that warrants further evaluation in clinically relevant models.