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

  1. Vera Gorbunovaa,1
  1. aDepartment of Biology, University of Rochester, Rochester, NY 14627;
  2. bDepartment of Biochemistry and Biophysics, School of Medicine and Dentistry, University of Rochester, Rochester, NY 14627; and
  3. cDepartment of Biological Sciences, Vanderbilt University, Nashville, TN 37232
  1. Edited by Eviatar Nevo, University of Haifa, Haifa, Israel, and approved September 16, 2009 (received for review May 12, 2009)

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 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.

Footnotes

  • ?1To whom correspondence should be addressed. E-mail: vgorbuno{at}mail.rochester.edu
  • Author contributions: A.S., C.H., J.A., M.F., M.B., Z.M., and V.G. designed research; A.S., C.H., J.A., M.F., M.B., and Z.M. performed research; K.C.C. contributed new reagents/analytic tools; A.S., C.H., J.A., M.F., M.B., Z.M., and V.G. analyzed data; and A.S. and V.G. wrote the paper.

  • The authors declare no conflict of interest.

  • This article is a PNAS Direct Submission.

  • See Commentary on page 19207.

  • This article contains supporting information online at www.danielhellerman.com/cgi/content/full/0905252106/DCSupplemental.

  • Received May 12, 2009.

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