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Published on: January 11, 2019

Pharmacologic inhibition of ALK5 causes selective induction of terminal differentiation in mouse keratinocytes

Lauren Mordasky Markell1, Katelyn E Masiuk, Nicholas Blazanin

  • 1The Pennsylvania State University, 201 Life Sciences Building, University Park, PA 16802, USA.

Molecular Cancer Research : MCR
|April 28, 2011
PubMed

Insights

SB431542 (SB) inhibits TGFβ signaling, enhancing keratinocyte cornification and cell death. While it suppresses benign tumors, SB-resistant cells may progress, suggesting complex effects in cancer development.

Area of Science:

  • Dermatology
  • Cancer Biology
  • Molecular Signaling

Background:

  • Transforming Growth Factor-beta (TGFβ) exhibits dual roles in cancer, acting as both a tumor suppressor and oncogene.
  • Previous studies indicated SB431542 (SB), a TGFβ type I receptor (ALK5) kinase inhibitor, suppresses benign epidermal tumors but promotes malignant conversion.

Purpose of the Study:

  • To investigate the effects of SB treatment on HRASV12G-induced keratinocyte hyperproliferation, cornified envelope formation, and cell death.
  • To elucidate the molecular mechanisms underlying SB's impact on keratinocyte differentiation and senescence in the context of HRASV12G expression.

Main Methods:

  • Utilized K5rTA/tetORASV12G bitransgenic keratinocytes and HRASV12G transgenic mice models.
  • Assessed keratinocyte hyperproliferation, cornified envelope formation, cell death, and expression of transglutaminase (TGM) 1, TGM3, small proline-rich protein (SPR) 1A, and SPR2H.
  • Evaluated the impact of SB and TGFβ1 on these processes, including responses in SB-resistant keratinocytes.

Main Results:

  • SB treatment did not alter HRASV12G-induced hyperproliferation but significantly enhanced cornified envelope formation and cell death.
  • SB increased the expression of TGM1, TGM3, SPR1A, and SPR2H, key components of the cornified envelope.
  • TGFβ1 suppressed cornified envelope formation, contrasting with SB's effects. SB-resistant, senescent-overcoming keratinocytes showed reduced p16(ink4a) and were growth-stimulated by SB.

Conclusions:

  • Pharmacologic blockade of TGFβ signaling via SB can inhibit preneoplastic lesion outgrowth by promoting keratinocyte differentiation and cell death.
  • However, SB may paradoxically drive progression in a subset of resistant keratinocytes, highlighting differential cellular responses to TGFβ inhibition.

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