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

ABSTRACT: 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 p27(Kip1). In contrast, early contact inhibition in naked mole-rat is associated with the induction of p16(Ink4a). Furthermore, we show that the roles of p16(Ink4a) and p27(Kip1) in the control of contact inhibition became temporally separated in this species: the early contact inhibition is controlled by p16(Ink4a), and regular contact inhibition is controlled by p27(Kip1). 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.

SUBMITTER: Seluanov A

PROVIDER: S-EPMC2780760 | biostudies-other | 2009 Nov

REPOSITORIES: biostudies-other

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

Seluanov Andrei A Hine Christopher C Azpurua Jorge J Feigenson Marina M Bozzella Michael M Mao Zhiyong Z Catania Kenneth C KC Gorbunova Vera V

Proceedings of the National Academy of Sciences of the United States of America 20091026 46

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 w ...[more]

PMID: 19858485

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Project description:BACKGROUND: The naked mole rats (NMRs) are small-sized underground rodents with plenty of unusual traits. Their life expectancy can be up to thirty years, more than seven times longer than laboratory rat. Furthermore, they are resistant to both congenital and experimentally induced cancer genesis. These peculiar physiological and pathological characteristics allow them to become a suitable model for cancer and aging research. RESULTS: In this paper, we carried out a genome-wide comparative analysis of rat and NMR using the recently published genome sequence of NMR. First, we identified all the rat-NMR orthologous genes and specific genes within each of them. The expanded and contracted numbers of protein families in NMR were also analyzed when compared to rat. Seven cancer-related protein families appeared to be significantly expanded, whereas several receptor families were found to be contracted in NMR. We then chose those rat genes that were inexistent in NMR and adopted KEGG pathway database to investigate the metabolic processes in which their proteins may be involved. These genes were significantly enriched in two rat cancer pathways, "Pathway in cancer" and "Bladder cancer". In the rat "Pathway in cancer", 9 out of 14 paths leading to evading apoptosis appeared to be affected in NMR. In addition, a significant number of other NMR-missing genes enriched in several cancer-related pathways have been known to be related to a variety of cancers, implying that many of them may be also related to tumorigenesis in mammals. Finally, investigation of sequence variations among orthologous proteins between rat and NMR revealed that significant fragment insertions/deletions within important functional domains were present in some NMR proteins, which might lead to expressional and/or functional changes of these genes in different species. CONCLUSIONS: Overall, this study provides insights into understanding the possible anti-cancer mechanisms of NMR as well as searching for new cancer-related candidate genes.

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

Publications

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

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