Abstract
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.
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Acknowledgements
The authors thank Dr. Kathleen Boyle and the Electron Microscope Facility at MCW for their technical assistance with the transmission electron microscopy. We gratefully thank Dr. Megan Harwig and Dr. Suresh Kumar for their help with the fluorescence microscopy. We thank Dr. Galina Petrova and the Children’s Research Institute & Cancer Flow Cytometry Core. Mass spectrometry analysis was performed by the Mass Spectrometry Core in the Cancer Center Translational Metabolomics Shared Resource. This research was completed in part with computational resources and technical support provided by the Research Computing Center at the Medical College of Wisconsin.
Funding
MBD was supported in part by grants from the National Cancer Institute R01CA226279 and continuing philanthropic support from the Hanis-Stepka-Rettig Endowed Chair in Cancer Research, and the Bobbie Nick Voss Charitable Foundation. MP was supported in part by a fellowship award from the Medical College of Wisconsin Cancer Center. DD was supported by an individual fellowship from the National Cancer Institute (F30CA291095) and is a member of the Medical Scientist Training Program at the Medical College of Wisconsin, which is partly supported by National Institutes of Health Training Grant T32 GM080202 from the National Institute of General Medical Sciences. CD was supported by the Medical College of Wisconsin Cancer Center and the University of Wisconsin-Milwaukee Undergraduate Research Experience Program. DS was supported in part by grants from the National Heart, Lung, and Blood Institute R01HL58012. JMB was supported by a predoctoral F31 award from the National Heart, Lung, and Blood Institute (F31HL178112). BCS was partly supported by a grant from the National Institute for General Medical Sciences R35GM12884. The content is solely the responsibility of the author(s) and does not necessarily represent the official views of the National Institutes of Health.
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MBD is a co-founder and has ownership and financial interests in Protein Foundry, LLC, and XLock Biosciences, Inc. BK has a composition-of-matter and application-of-use patent on the manufacture and use of mito-metformin in cancer (USPTO 62/779,795). Chemical modifications of mitochondria-targeted compounds, including those described herein, are covered by a provisional US Patent, U.S. Application No. 63/285,374, to MBD, RFK, and BCS. MP was supported in part by a fellowship award from the Medical College of Wisconsin Cancer Center. DD, JMB, DS, and BCS have received financial support from the NIH. All other authors declare no potential financial conflict of interest.
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All procedures and animal experiments were reviewed and approved by the Institutional Animal Care and Use Committee (IACUC) at Medical College of Wisconsin and performed in accordance with the approved Animal Use Agreement AUA000076.
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Poimenidou, M., Bobek, J.M., Drouillard, D. et al. Mitochondria-targeted metformin analogs activate the ER stress-unfolded protein response pathway to drive apoptosis in pancreatic cancer. Cell Death Dis (2026). https://doi.org/10.1038/s41419-026-08859-y
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DOI: https://doi.org/10.1038/s41419-026-08859-y
