Pancreatic cancers require autophagy for tumor growth
Open accessAbstract
Macroautophagy (autophagy) is a regulated catabolic pathway to degrade cellular organelles and macromolecules. The role of autophagy in cancer is complex and may differ depending on tumor type or context. Here we show that pancreatic cancers have a distinct dependence on autophagy. Pancreatic cancer primary tumors and cell lines show elevated autophagy under basal conditions. Genetic or pharmacologic inhibition of autophagy leads to increased reactive oxygen species, elevated DNA damage, and a metabolic defect leading to decreased mitochondrial oxidative phosphorylation. Together, these ultimately result in significant growth suppression of pancreatic cancer cells in vitro. Most importantly, inhibition of autophagy by genetic means or chloroquine treatment leads to robust tumor regression and prolonged survival in pancreatic cancer xenografts and genetic mouse models. These results suggest that, unlike in other cancers where autophagy inhibition may synergize with chemotherapy or targeted agents by preventing the up-regulation of autophagy as a reactive survival mechanism, autophagy is actually required for tumorigenic growth of pancreatic cancers de novo, and drugs that inactivate this process may have a unique clinical utility in treating pancreatic cancers and other malignancies with a similar dependence on autophagy. As chloroquine and its derivatives are potent inhibitors of autophagy and have been used safely in human patients for decades for a variety of purposes, these results are immediately translatable to the treatment of pancreatic cancer patients, and provide a much needed, novel vantage point of attack.
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Pancreatic cancer cells exhibit increased lysosome biogenesis and constitutive engagement of autophagy.
“increased biogenesis of lysosomes and constitutive engagement of the autophagy “self-eating” recycling program206”
From Pancreatic cancer: Advances and challenges (2023) · cites this paper as [206]
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- Authors
- Yang, S., Wang, X., Contino, G., Liesa, M., Sahin, E., Ying, H., Bause, A., Li, Y., Stommel, J. M., Dell'Antonio, G., Mautner, J., Tonon, G., Haigis, M., Shirihai, O. S., Doglioni, C., Bardeesy, N., & Kimmelman, A. C.
- Affiliations
- Harvard University (US)
- Boston University (US)
- Helmholtz Munich (DE)
- ORCID
- Venue
- Genes & Development
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2011-03-15
- Volume
- 25
- Issue
- 7
- Pages
- 717-729
- ISSN
- 0890-9369 (ISSN-L)
- 1549-5477
- PMC
- PMC3070934
- OpenAlex
- W2102690338
- Cited by
- 1,498
- References
- 56
- Citations by year
- 2026: 53 · 2025: 65 · 2024: 78 · 2023: 94 · 2022: 117 · 2021: 141 · 2020: 119 · 2019: 98 · 2018: 118 · 2017: 108 · 2016: 109 · 2015: 92 · 2014: 96 · 2013: 99 · 2012: 72
- Type
- posted content
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Genes & Development (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- BOA (University of Milano-Bicocca) (submittedVersion, other-oa)
- Archivio Istituzionale della Ricerca - Università Vita-Salute San Raffaele (submittedVersion)
- mediaTUM – the media and publications repository of the Technical University Munich (Technical University Munich) (submittedVersion)
- University of Birmingham Research Portal (University of Birmingham) (submittedVersion)
- Funders
- National Cancer Institute (P50CA127003, P01CA117969)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK035914, R01DK056690)
- Topics
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Keywords
- pancreatic cancer, autophagy, autophagy inhibition, chloroquine, reactive oxygen species, DNA damage, mitochondrial oxidative phosphorylation, tumor growth, tumor regression, xenografts, cancer metabolism
- MeSH terms
- Animals, Antineoplastic Agents, Autophagy, Chloroquine, DNA Damage, Humans, Mice, Nude, Pancreatic Neoplasms, Random Allocation, Transplantation, Heterologous, Reactive Oxygen Species, Carcinoma, Pancreatic Ductal, RNA Interference, Cell Line, Tumor, Mice
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