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<p>Pancreatic tumors frequently develop in nutrient-poor microenvironments due to impaired perfusion, forcing cancer cells to engage in metabolic adaptation for survival. This study identified the upregulation of transketolase-like 1 (TKTL1) as a nutrient-stress–responsive factor associated with metabolic adaptation of pancreatic cancer cells under amino-acid starvation, particularly glutamine scarcity. In particular, we found that TKTL1 induction was specifically observed in cancer cells and not in normal pancreatic ductal cells. Functional assays showed that TKTL1 overexpression increased proliferative capacity and tumor growth, whereas its knockdown attenuated these phenotypes and reduced cancer cell fitness under nutrient stress. Although TKTL1 exhibits weak intrinsic enzymatic activity, our data support a functional association with transketolase (TKT), accompanied by increased total transketolase activity. Protein–protein interaction assays further indicated that TKTL1 binds to TKT more prominently under nutrient deprivation than under nutrient-rich conditions. Furthermore, transcriptional analyses and NF-κB inhibition experiments suggest that TKTL1 upregulation is partially regulated by the NF-κB/p50 axis. Together, these findings are consistent with a model in which TKTL1 contributes to metabolic adaptation and stress tolerance in nutrient-deprived pancreatic cancer cells, in part through interaction with TKT, and suggest that the TKTL1 axis may represent a context-dependent therapeutic target in nutrient-limited tumors.</p>

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TKTL1 mediates metabolic adaptation and stress resistance in pancreatic cancer cells under nutrient-deprived conditions

  • 期刊论文

  • 发表日期：

    2026年7月30日

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  • Takefumi Onodera,
  • Shuichi Sakamoto,
  • Shunichi Ohba,
  • Manabu Kawada,
  • Isao Momose

摘要

Pancreatic tumors frequently develop in nutrient-poor microenvironments due to impaired perfusion, forcing cancer cells to engage in metabolic adaptation for survival. This study identified the upregulation of transketolase-like 1 (TKTL1) as a nutrient-stress–responsive factor associated with metabolic adaptation of pancreatic cancer cells under amino-acid starvation, particularly glutamine scarcity. In particular, we found that TKTL1 induction was specifically observed in cancer cells and not in normal pancreatic ductal cells. Functional assays showed that TKTL1 overexpression increased proliferative capacity and tumor growth, whereas its knockdown attenuated these phenotypes and reduced cancer cell fitness under nutrient stress. Although TKTL1 exhibits weak intrinsic enzymatic activity, our data support a functional association with transketolase (TKT), accompanied by increased total transketolase activity. Protein–protein interaction assays further indicated that TKTL1 binds to TKT more prominently under nutrient deprivation than under nutrient-rich conditions. Furthermore, transcriptional analyses and NF-κB inhibition experiments suggest that TKTL1 upregulation is partially regulated by the NF-κB/p50 axis. Together, these findings are consistent with a model in which TKTL1 contributes to metabolic adaptation and stress tolerance in nutrient-deprived pancreatic cancer cells, in part through interaction with TKT, and suggest that the TKTL1 axis may represent a context-dependent therapeutic target in nutrient-limited tumors.