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Cited by 50Autophagy in Disease and TherapyPI3K/AKT/mTOR signaling in cancerMetabolism, Diabetes, and Cancer

Autophagy restricts proliferation driven by oncogenic phosphatidylinositol 3-kinase in three-dimensional culture

Open access
Chen, N, Eritja, N, Lock, R, Debnath, J·2013·Oncogene
DOI 10.1038/onc.2012.277PMC PMC3470740
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Abstract

Autophagy is a tightly regulated lysosomal self-digestion process that can both promote and impede tumorigenesis. Here, we utilize a three-dimensional (3D) culture model to address how interactions between autophagy and the phosphatidylinositol 3-kinase(PI3K)/Akt/mammalian target of rapamycin pathway impact the malignant behavior of cells carrying a tumor-derived, activating mutation in PI3K (PI3K-H1047R). In this model, autophagy simultaneously mediates tumor-suppressive and -promoting functions within individual glandular structures. In 3D culture, constitutive PI3K activation overcomes proliferation arrest and promotes resistance to anoikis in the luminal space, resulting in aberrant structures with filled lumen. Inhibiting autophagy in PI3K-H1047R structures triggers luminal cell apoptosis, resulting in lumen clearance. At the same time, autophagy gene depletion strongly enhances PI3K-H1047R cell proliferation during 3D morphogenesis, revealing an unexpected role for autophagy in restricting proliferation driven by PI3K activation. Intriguingly, overexpression of the autophagy cargo receptor p62/SQSTM1 in PI3K-H1047R cells is sufficient to enhance cell proliferation, activate the extracellular signal-related kinase/mitogen-activated protein kinase pathway and to promote epidermal growth factor-independent proliferation in 3D culture. Overall, these results indicate that autophagy antagonizes specific aspects of oncogenic PI3K transformation, with the loss of autophagy promoting proliferation.

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  • Multiple research results have shown that autophagy protects cells exposed to various forms of stress, including nutrient deprivation, growth factor regression, endoplasmic reticulum stress, and ischemia.

    “In addition, multiple research results have shown that autophagy protects cells exposed to various forms of stress, including nutrient deprivation, growth factor regression, endoplasmic reticulum stress, and ischemia.[23–25]”

    From Autophagy, not apoptosis, plays a role in lumen formation of eccrine gland organoids (2022) · cites this paper as [25]

    The Introduction (page unavailable) says autophagy commonly promotes survival under stresses including nutrient starvation and ER stress. It does not identify growth-factor regression or ischemia among those stresses; it discusses hypoxia instead. The Discussion also reports a survival role for autophagy during extracellular-matrix deprivation, a different condition. (LLM, conf=0.88)

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Research works printed but not linked: 28

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Authors
Chen, N., Eritja, N., Lock, R., & Debnath, J.
Affiliations
  • University of California, San Francisco (US)
  • Universitat de Lleida (ES)
Corresponding author
Debnath, J
ORCID
Venue
Oncogene
Publisher
Springer Science and Business Media LLC
Published
2012-07-09
Volume
32
Issue
20
Pages
2543-2554
ISSN
  • 0950-9232 (ISSN-L)
  • 1476-5594
DOI
10.1038/onc.2012.277
PMC
PMC3470740
OpenAlex
W2013806654
Cited by
50
References
6
Citations by year
2026: 2 · 2024: 2 · 2023: 2 · 2022: 6 · 2021: 7 · 2020: 3 · 2019: 1 · 2018: 4 · 2017: 2 · 2016: 4 · 2015: 5 · 2014: 8 · 2013: 4
FWCI
4.07
Type
journal article
Language
en
Open access
Licence
Locations
  • Oncogene (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
  • eScholarship (California Digital Library) (submittedVersion, cc-by-nc-nd)
Funders
National Cancer Institute (CA126792-S1, R01CA126792)
Topics
  • Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
Keywords
autophagy, phosphatidylinositol 3-kinase, PI3K/AKT/mTOR pathway, cell proliferation, 3D cell culture, anoikis resistance, apoptosis, p62, MAPK/ERK pathway, tumor morphogenesis, tumor suppression
MeSH terms
Sequestosome-1 Protein, Mechanistic Target of Rapamycin Complex 1, Autophagy, Cell Line, Cell Transformation, Neoplastic, Humans, Hydroxychloroquine, Lysosomes, Mutation, Apoptosis, Cell Culture Techniques, Sirolimus, Mitogen-Activated Protein Kinases, Multiprotein Complexes, Adaptor Proteins, Signal Transducing, Cell Proliferation, Phosphatidylinositol 3-Kinase, TOR Serine-Threonine Kinases

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