Report

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

Volume 11, Issue 19   October 1, 2012
Pages 3599 - 3610
http://dx.doi.org/10.4161/cc.21884
Keywords: CDK inhibitors, PD0332991, aging, autophagy, cancer metabolism, cancer-associated fibroblast, cell cycle arrest, glycolysis, mitophagy, senescence, tumor initiation, tumor stroma
Authors: Claudia Capparelli, Barbara Chiavarina, Diana Whitaker-Menezes, Timothy G. Pestell, Richard G. Pestell, James Hulit, Sebastiano Andò, Anthony Howell, Ubaldo E. Martinez-Outschoorn, Federica Sotgia and Michael P. Lisanti

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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 (H₂O₂) 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.

Received: August 2, 2012; Accepted: August 19, 2012; Published Online: August 30, 2012

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