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Tumor necrosis factor receptor 1/c-Jun-NH2-kinase signaling promotes human neoplasia

Jennifer Y Zhang1, Amy E Adams, Todd W Ridky

  • 1Department of Medicine, Division of Dermatology, Duke University School of Medicine, Trent Drive, Durham, NC 27710, USA. Jennifer.zhang@duke.edu

Cancer Research
|April 19, 2007
PubMed

Insights

The tumor necrosis factor alpha receptor (TNFR1) pathway, including MKK7/JNK/AP1, drives human squamous cell carcinoma (SCC) development. Inhibiting this cascade halts tumor growth, revealing a promising therapeutic target for epithelial cancers.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Signaling

Background:

  • The tumor necrosis factor alpha receptor 1 (TNFR1) pathway is implicated in cellular responses.
  • Mitogen-activated protein kinase kinase 7 (MKK7)/c-Jun-NH(2)-kinase (JNK)/activator protein 1 (AP1) is a key downstream signaling cascade activated by TNFR1.
  • Aberrant signaling pathways are frequently observed in various cancers, including squamous cell carcinomas (SCC).

Purpose of the Study:

  • To investigate the role of the TNFR1/MKK7/JNK/AP1 cascade in the pathogenesis of human squamous cell carcinomas (SCC).
  • To determine the oncogenic potential of JNK pathway activation in human epidermal tissue.
  • To evaluate the therapeutic efficacy of targeting components of this cascade in human neoplasia.

Main Methods:

  • Analysis of JNK activation in human SCC samples.
  • Experimental manipulation of oncogenic Ras and JNK pathway components in human epidermal models.
  • Inhibition of TNFR1, MKK7, JNK, and AP1 using genetic, pharmacologic, and antibody-mediated strategies.
  • Assessment of tumor formation and invasiveness in treated and untreated models.

Main Results:

  • JNK activation was detected in a majority of spontaneous human SCCs.
  • JNK pathway activation bypassed oncogenic Ras-induced cell cycle arrest and cooperated with Ras to induce SCC formation in human epidermis.
  • Inhibition of TNFR1, MKK7, JNK, or AP1 effectively abolished invasive human epidermal neoplasia in a tumor cell-autonomous manner.

Conclusions:

  • The TNFR1/MKK7/JNK/AP1 signaling cascade possesses oncogenic potency and plays a critical role in promoting human squamous cell carcinoma development.
  • Targeting this pathway offers a potential therapeutic strategy for human epithelial cancers.

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