ArticleCell cycle (Georgetown, Tex.)2012
CDK inhibitors (p16/p19/p21) induce senescence and autophagy in cancer-associated fibroblasts, "fueling" tumor growth via paracrine interactions, without an increase in neo-angiogenesis.
Article in Cell cycle (Georgetown, Tex.), 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 133 papers.
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Who cites it
133 citing papers in PubMed, 224 citations in OpenAlex.
- Cellular senescence and regulated cell death in cancer: mechanisms, cross-regulatory networks and therapeutic implications.Journal of hematology & oncology · 2026Review
- Autophagy in Osx1-Cre-targeted cells is essential for development, growth, and maintenance of bone.Bone reports · 2026Article
- Tumor cells escape from therapy-induced senescence: from molecular mechanisms to targeted intervention.Biology direct · 2026Review
- LARS regulates cellular senescence and autophagy in liver cancer cells.Cell death & disease · 2026Article
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- Molecular Mechanisms Underlying Reproductive Dysfunction in Polycystic Ovary Syndrome.Reproductive sciences (Thousand Oaks, Calif.) · 2026Review
- Colonic inflammatory response in a D-galactose-induced aging model: elevated IL-1β expression.Journal of molecular histology · 2026Article
- Senomorphic Activity of a Novel Standardized Propolis Extract in Human Dermal Fibroblasts: Molecular Insights Into Clinically Proven Anti-Wrinkle Efficacy.Journal of cosmetic dermatology · 2026Article
- CDKN1A/p21 Influences the Survival and Expansion of Breast Cancer Stem Cells after Oxidative Damage.Oncology research · 2026Article
- The drug discovery and therapeutic nano-strategies targeting cellular senescence.Materials today. Bio · 2025Review
- Review
- Determination of ADP/ATP translocase isoform ratios in malignancy and cellular senescence.Molecular oncology · 2025Article
- Senescent macrophages in cancer: roles in tumor progression and treatment opportunities.Cancer biology & medicine · 2025Review
- A Positive Feedback DNA-PK/MYT1L-CXCR1-ERK1/2 Proliferative Signaling Loop in Glioblastoma.International journal of molecular sciences · 2025Article
- Histopathologic and Molecular Insights Following the Management of Ameloblastomas via Targeted Therapies - Pathological and Clinical Perspectives.Head and neck pathology · 2024Article
- Senescence-like Phenotype After Chronic Exposure to Isoproterenol in Primary Quiescent Immune Cells.Biomolecules · 2024Article
- Blocking ACSL6 Compromises Autophagy via FLI1-Mediated Downregulation of COLs to Radiosensitize Lung Cancer.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2024Article
- Chemical genetic screens reveal defective lysosomal trafficking as synthetic lethal with NF1 loss.Journal of cell science · 2024Article
- Review
- The emerging and diverse roles of F-box proteins in spermatogenesis and male infertility.Cell regeneration (London, England) · 2024Review
73 more citing papers are in PubMed but not listed here.
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Authors and funding
11 authors at 6 institutions in 3 countries.
Funding
Abstract
Here, we investigated the compartment-specific role of cell cycle arrest and senescence in breast cancer tumor growth. For this purpose, we generated a number of hTERT-immortalized senescent fibroblast cell lines overexpressing CDK inhibitors, such as p16(INK4A), p19(ARF) or p21(WAF1/CIP1). Interestingly, all these senescent fibroblast cell lines showed evidence of increased susceptibility toward the induction of autophagy (either at baseline or after starvation), as well as significant mitochondrial dysfunction. Most importantly, these senescent fibroblasts also dramatically promoted tumor growth (up to ~2-fold), without any comparable increases in tumor angiogenesis. Conversely, we generated human breast cancer cells (MDA-MB-231 cells) overexpressing CDK inhibitors, namely p16(INK4A) or p21(WAF1/CIP1). Senescent MDA-MB-231 cells also showed increased expression of markers of cell cycle arrest and autophagy, including β-galactosidase, as predicted. Senescent MDA-MB-231 cells had retarded tumor growth, with up to a near 2-fold reduction in tumor volume. Thus, the effects of CDK inhibitors are compartment-specific and are related to their metabolic effects, which results in the induction of autophagy and mitochondrial dysfunction. Finally, induction of cell cycle arrest with specific inhibitors (PD0332991) or cellular stressors [hydrogen peroxide (H(2)O(2)) or starvation] indicated that the onset of autophagy and senescence are inextricably linked biological processes. The compartment-specific induction of senescence (and hence autophagy) may be a new therapeutic target that could be exploited for the successful treatment of human breast cancer patients.
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