ArticleOncogene2021
SMAD4 loss limits the vulnerability of pancreatic cancer cells to complex I inhibition via promotion of mitophagy.
Article in Oncogene, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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Who cites it
24 citing papers in PubMed, 29 citations in OpenAlex.
- FOXO1 Promotes Mitophagy in Granulosa Cells by Targeting the METTL3/SMAD4 axis.Cell biochemistry and biophysics · 2026Article
- Mitophagy interacts with mitochondrial dynamics and biogenesis, acting as a double-edged sword in digestive cancer.iScience · 2026Review
- Imbalances of mitochondrial dynamics in solid tumors.Oncogenesis · 2026Review
- Review
- Molecular regulation of mitophagy signaling in tumor microenvironment and its targeting for cancer therapy.Cytokine & growth factor reviews · 2025Review
- The interplay between driver mutation and oxidative stress in colorectal cancer: from pathogenesis to therapeutics.Journal of translational medicine · 2025Review
- Metabolic plasticity in pancreatic cancer: The mitochondrial connection.Molecular metabolism · 2025Review
- Modeling Krebs cycle from liver, heart and hepatoma mitochondria, supported Complex I as target for specific inhibition of cancer cell proliferation.Frontiers in oncology · 2025Article
- PRMT1 promotes epigenetic reprogramming associated with acquired chemoresistance in pancreatic cancer.Cell reports · 2024Article
- KDM5B promotes SMAD4 loss-driven drug resistance through activating DLG1/YAP to induce lipid accumulation in pancreatic ductal adenocarcinoma.Cell death discovery · 2024Article
- A stumbling block in pancreatic cancer treatment: drug resistance signaling networks.Frontiers in cell and developmental biology · 2024Review
- SMAD Proteins in TGF-β Signalling Pathway in Cancer: Regulatory Mechanisms and Clinical Applications.Diagnostics (Basel, Switzerland) · 2023Review
- The role of epithelial-mesenchymal transition and autophagy in pancreatic ductal adenocarcinoma invasion.Cell death & disease · 2023Review
- Mitochondria-Related Transcriptome Characterization Associated with the Immune Microenvironment, Therapeutic Response and Survival Prediction in Pancreatic Cancer.International journal of molecular sciences · 2023Article
- Editorial: The effects of mitochondrial dysfunction on the cell cycle.Frontiers in cell and developmental biology · 2023Article
- Clinical and Molecular Attributes and Evaluation of Pancreatic Cystic Neoplasm.Biochimica et biophysica acta. Reviews on cancer · 2023Review
- Exploiting the molecular subtypes and genetic landscape in pancreatic cancer: the quest to find effective drugs.Frontiers in genetics · 2023Review
- The mechanisms of action of mitochondrial targeting agents in cancer: inhibiting oxidative phosphorylation and inducing apoptosis.Frontiers in pharmacology · 2023Review
- Multiple roles of mothers against decapentaplegic homolog 4 in tumorigenesis, stem cells, drug resistance, and cancer therapy.World journal of stem cells · 2022Review
- CircGSAP regulates the cell cycle of pulmonary microvascular endothelial cells via the miR-942-5p sponge in pulmonary hypertension.Frontiers in cell and developmental biology · 2022Article
Corrections and comments
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Authors and funding
12 authors at 5 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Pancreatic cancer is one of the deadliest forms of cancer, which is attributed to lack of effective treatment options and drug resistance. Mitochondrial inhibitors have emerged as a promising class of anticancer drugs, and several inhibitors of the electron transport chain (ETC) are being clinically evaluated. We hypothesized that resistance to ETC inhibitors from the biguanide class could be induced by inactivation of SMAD4, an important tumor suppressor involved in transforming growth factor β (TGFβ) signaling, and associated with altered mitochondrial activity. Here we show that, paradoxically, both TGFβ-treatment and the loss of SMAD4, a downstream member of TGFβ signaling cascade, induce resistance to biguanides, decrease mitochondrial respiration, and fragment the mitochondrial network. Mechanistically, the resistance of SMAD4-deficient cells is mediated by increased mitophagic flux driven by MAPK/ERK signaling, whereas TGFβ-induced resistance is autophagy-independent and linked to epithelial-to-mesenchymal transition (EMT). Interestingly, mitochondria-targeted tamoxifen, a complex I inhibitor under clinical trial, overcomes resistance mediated by SMAD4-deficiency or TGFβ signaling. Our data point to differential mechanisms underlying the resistance to treatment in PDAC arising from TGFβ signaling and SMAD4 loss, respectively. The findings will help the development of mitochondria-targeted therapy for pancreatic cancer patients with SMAD4 as a plausible predictive marker.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.