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Rap1GAP inhibits tumor growth in oropharyngeal squamous cell carcinoma

Zhaocheng Zhang1, Raj S Mitra, Bradley S Henson

  • 1Department of Oral Medicine, Pathology, and Oncology, University of Michigan, School of Dentistry, Ann Arbor, MI 48109-1078, USA.

The American Journal of Pathology
|January 27, 2006
PubMed

Insights

Rap1 GTPase activating protein (rap1GAP) acts as a tumor suppressor in squamous cell carcinoma (SCC). Overexpressing rap1GAP in SCC cells reduced tumor growth and proliferation by inhibiting active Rap1 signaling.

Area of Science:

  • Oncology
  • Cell Biology
  • Molecular Biology

Background:

  • Rap1, a growth regulatory protein, is highly expressed in human squamous cell carcinoma (SCC).
  • Rap1 GTPase activating protein (rap1GAP) inactivates Rap1 and may regulate proliferation.
  • Evidence suggests rap1GAP could function as a tumor suppressor in SCC.

Purpose of the Study:

  • To investigate the potential tumor suppressor role of rap1GAP in SCC.
  • To determine if rap1GAP regulates proliferation and Rap1 signaling in SCC.

Main Methods:

  • Pull-down assays to measure active GTP-bound Rap1.
  • Transfection of SCC cells with rap1GAP, rap1A, rap1B, or control vectors.
  • Cell cycle analysis using nocodazole and assessment of cell cycle regulatory proteins (cyclin D1, cdk4, cdk6).
  • Tumorigenicity assays in nude mice.

Main Results:

  • Active GTP-bound Rap1 was upregulated in SCC compared to normal keratinocytes.
  • Rap1GAP expression in SCC cells down-regulated active Rap1, ERK activation, and proliferation.
  • Rap1GAP-transfected SCC cells exhibited slower cell cycle progression and reduced levels of cyclin D1, cdk4, and cdk6.
  • SCC cells expressing rap1GAP formed significantly smaller tumors in vivo.

Conclusions:

  • Rap1GAP functions as a tumor suppressor in SCC.
  • Rap1GAP inhibits SCC proliferation and tumor growth by down-regulating Rap1 signaling.
  • Rap1GAP represents a potential therapeutic target for SCC.

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