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Sulforaphane covalently interacts with the transglutaminase 2 cancer maintenance protein to alter its structure and

Ellen A Rorke1, Gautam Adhikary2, Henryk Szmacinski2

  • 1Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, Maryland, USA.

Molecular Carcinogenesis
|October 5, 2021
PubMed

Insights

Sulforaphane (SFN) targets Type 2 transglutaminase (TG2), a cancer survival protein. SFN inhibits TG2

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cancer Research

Background:

  • Type 2 transglutaminase (TG2) is crucial for cancer cell survival, particularly in epidermal squamous cell carcinoma.
  • TG2 has two conformations: closed (GTP-binding/GTPase active) and open (transamidase active).
  • The closed conformation's GTPase activity promotes aggressive cancer phenotypes, making TG2 an attractive therapeutic target.

Purpose of the Study:

  • To investigate if sulforaphane (SFN), a diet-derived compound, directly targets TG2.
  • To determine the mechanism by which SFN affects TG2 activity and conformation.
  • To establish TG2 as a direct anticancer target of SFN in epidermal squamous cell carcinoma.

Main Methods:

  • Utilized a biotin-tagged SFN analog (Biotin-ITC) for covalent binding studies.
  • Employed kinetic analysis to assess TG2 activity inhibition.
  • Examined TG2 conformation shifts using biochemical assays in cell extracts and intact cancer cells.

Main Results:

  • SFN covalently and irreversibly binds to recombinant TG2, inhibiting its transamidase activity.
  • SFN treatment shifts TG2 to an open/extended conformation, partially inhibiting GTP binding.
  • SFN treatment of cancer cells inhibits TG2 transamidase activity and induces the open conformation.

Conclusions:

  • Identifies TG2 as a direct molecular target of sulforaphane (SFN).
  • Demonstrates that SFN modulates TG2 conformation and activity, impacting cancer cell survival.
  • Provides a mechanistic basis for SFN's anticancer effects in epidermal squamous cell carcinoma.
Keywords:
GTP binding proteincancer preventioncancer stem cellepidermal squamous cell carcinomasulforaphanetransamidase activitytransglutaminase 2

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