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<p>Accumulating evidence indicates that evasion of apoptosis and metabolic reprogramming are necessary for pancreatic cancer growth, early invasion, and chemotherapeutic resistance. Building on our prior work, we investigated the anti-tumor potential of a rationally designed mitochondria-targeted variant of the anti-diabetic drug metformin, Mito-Met<sub>10</sub>, in cell culture models and orthotopic xenografts. Using MALDI-mass spectrometry imaging, therapeutic concentrations of fluorinated Mito-Met<sub>10</sub> were shown to preferentially localize within pancreatic tumors relative to adjacent tissue and liver. Treatment suppressed tumor growth, reduced tumor weights, and increased apoptosis in vivo. Murine and human pancreatic cancer cells demonstrated potent anti-proliferative activity, with low micromolar IC<sub>50</sub> values, and a concomitant induction of apoptotic programmed cell death in vitro. Seahorse metabolic flux analysis revealed reduced basal and ATP-linked mitochondrial respiration following Mito-Met<sub>10</sub> treatment without a compensatory increase in glycolysis. Unbiased bulk RNA sequencing revealed significant enrichment of endoplasmic reticulum stress and unfolded protein response pathways, validated by qPCR across pancreatic cancer models, with broad upregulation of UPR-associated genes, establishing that Mito-Met<sub>10</sub> activation of this stress response is conserved. Mito-Met<sub>10</sub> caused extensive cytoplasmic vacuolization, mitochondrial swelling, and loss of mitochondrial membrane potential, indicative of severe organelle damage. Mito-Met<sub>10</sub> activated PERK-eIF2α-ATF4-CHOP signaling, including upregulation of ATF4 and downstream pro-apoptotic transcriptional programs. Pharmacologic inhibition of ISR abrogated apoptotic signaling, demonstrating that PERK-eIF2α-ATF4-CHOP-mediated ISR activation functionally contributes to the anti-tumor effects of Mito-Met<sub>10</sub>. Consistent with these findings, orthotopic tumors from Mito-Met<sub>10</sub>-treated mice exhibited increased nuclear ATF4 staining compared with vehicle controls. Collectively, this study links mitochondrial stress to ER stress-associated apoptosis and identifies mitochondrial stress as a tractable vulnerability that can be manipulated to positively engage anti-tumor responses in pancreatic cancer.</p><p></p>

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Mitochondria-targeted metformin analogs activate the ER stress-unfolded protein response pathway to drive apoptosis in pancreatic cancer

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月22日

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  • Maria Poimenidou,
  • Jordan M. Bobek,
  • Donovan Drouillard,
  • Tyler Harris,
  • Elisabeth Solis,
  • Chad Darnell,
  • Donna McAllister,
  • Robert F. Keyes,
  • Mayumi Ishihara-Aoki,
  • Kazuhiro Aoki,
  • Daisy Sahoo,
  • Balaraman Kalyanaraman,
  • Brian C. Smith,
  • Michael B. Dwinell

摘要

Accumulating evidence indicates that evasion of apoptosis and metabolic reprogramming are necessary for pancreatic cancer growth, early invasion, and chemotherapeutic resistance. Building on our prior work, we investigated the anti-tumor potential of a rationally designed mitochondria-targeted variant of the anti-diabetic drug metformin, Mito-Met10, in cell culture models and orthotopic xenografts. Using MALDI-mass spectrometry imaging, therapeutic concentrations of fluorinated Mito-Met10 were shown to preferentially localize within pancreatic tumors relative to adjacent tissue and liver. Treatment suppressed tumor growth, reduced tumor weights, and increased apoptosis in vivo. Murine and human pancreatic cancer cells demonstrated potent anti-proliferative activity, with low micromolar IC50 values, and a concomitant induction of apoptotic programmed cell death in vitro. Seahorse metabolic flux analysis revealed reduced basal and ATP-linked mitochondrial respiration following Mito-Met10 treatment without a compensatory increase in glycolysis. Unbiased bulk RNA sequencing revealed significant enrichment of endoplasmic reticulum stress and unfolded protein response pathways, validated by qPCR across pancreatic cancer models, with broad upregulation of UPR-associated genes, establishing that Mito-Met10 activation of this stress response is conserved. Mito-Met10 caused extensive cytoplasmic vacuolization, mitochondrial swelling, and loss of mitochondrial membrane potential, indicative of severe organelle damage. Mito-Met10 activated PERK-eIF2α-ATF4-CHOP signaling, including upregulation of ATF4 and downstream pro-apoptotic transcriptional programs. Pharmacologic inhibition of ISR abrogated apoptotic signaling, demonstrating that PERK-eIF2α-ATF4-CHOP-mediated ISR activation functionally contributes to the anti-tumor effects of Mito-Met10. Consistent with these findings, orthotopic tumors from Mito-Met10-treated mice exhibited increased nuclear ATF4 staining compared with vehicle controls. Collectively, this study links mitochondrial stress to ER stress-associated apoptosis and identifies mitochondrial stress as a tractable vulnerability that can be manipulated to positively engage anti-tumor responses in pancreatic cancer.