Hypersensitivity to contact inhibition provides a clue to cancer resistance of naked mole-rat

The naked mole-rat is the longest living rodent with a maximum lifespan exceeding 28 years. In addition to its longevity, naked mole-rats have an extraordinary resistance to cancer as tumors have never been observed in these rodents. Furthermore, we show that a combination of activated Ras and SV40...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2009-11, Vol.106 (46), p.19352-19357
Main Authors: Seluanov, Andrei, Hine, Christopher, Azpurua, Jorge, Feigenson, Marina, Bozzella, Michael, Mao, Zhiyong, Catania, Kenneth C, Gorbunova, Vera
Format: Article
Language:English
Subjects:
Animals
Antigens, Polyomavirus Transforming - genetics
Antigens, Polyomavirus Transforming - metabolism
Apoptosis
Biological Sciences
Cancer
Cell Communication
Cell culture techniques
Cell growth
Cell Proliferation
Cell Transformation, Neoplastic
Cells
Cellular senescence
Cyclin-Dependent Kinase Inhibitor p16 - metabolism
Cyclin-Dependent Kinase Inhibitor p27 - metabolism
Disease Models, Animal
Fibroblasts
Fibroblasts - metabolism
Fibroblasts - pathology
Humans
Immune system
Longevity
Lungs
Mice
Mole Rats
Neoplasms - metabolism
Neoplasms - pathology
Proto-Oncogene Proteins p21(ras) - genetics
Proto-Oncogene Proteins p21(ras) - metabolism
Retinoblastoma Protein - metabolism
Rodents
Tumor Suppressor Protein p53 - metabolism
Tumors
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Summary:The naked mole-rat is the longest living rodent with a maximum lifespan exceeding 28 years. In addition to its longevity, naked mole-rats have an extraordinary resistance to cancer as tumors have never been observed in these rodents. Furthermore, we show that a combination of activated Ras and SV40 LT fails to induce robust anchorage-independent growth in naked mole-rat cells, while it readily transforms mouse fibroblasts. The mechanisms responsible for the cancer resistance of naked mole-rats were unknown. Here we show that naked mole-rat fibroblasts display hypersensitivity to contact inhibition, a phenomenon we termed "early contact inhibition." Contact inhibition is a key anticancer mechanism that arrests cell division when cells reach a high density. In cell culture, naked mole-rat fibroblasts arrest at a much lower density than those from a mouse. We demonstrate that early contact inhibition requires the activity of p53 and pRb tumor suppressor pathways. Inactivation of both p53 and pRb attenuates early contact inhibition. Contact inhibition in human and mouse is triggered by the induction of p27Kip¹. In contrast, early contact inhibition in naked mole-rat is associated with the induction of p16Ink⁴a. Furthermore, we show that the roles of p16Ink⁴a and p27Kip¹ in the control of contact inhibition became temporally separated in this species: the early contact inhibition is controlled by p16Ink⁴a, and regular contact inhibition is controlled by p27Kip¹. We propose that the additional layer of protection conferred by two-tiered contact inhibition contributes to the remarkable tumor resistance of the naked mole-rat.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0905252106