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Transglutaminase-2: evolution from pedestrian protein to a promising therapeutic target

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Abstract

The ability of cancer cells to metastasize represents the most devastating feature of cancer. Currently, there are no specific biomarkers or therapeutic targets that can be used to predict the risk or to treat metastatic cancer. Many recent reports have demonstrated elevated expression of transglutaminase 2 (TG2) in multiple drug-resistant and metastatic cancer cells. TG2 is a multifunctional protein mostly known for catalyzing Ca2+-dependent -acyl transferase reaction to form protein crosslinks. Besides this transamidase activity, many Ca2+-independent and non-enzymatic activities of TG2 have been identified. Both, the enzymatic and non-enzymatic activities of TG2 have been implicated in diverse pathophysiological processes such as wound healing, cell growth, cell survival, extracellular matrix modification, apoptosis, and autophagy. Tumors have been frequently referred to as ‘wounds that never heal’. Based on the observation that TG2 plays an important role in wound healing and inflammation is known to facilitate cancer growth and progression, we discuss the evidence that TG2 can reprogram inflammatory signaling networks that play fundamental roles in cancer progression. TG2-regulated signaling bestows on cancer cells the ability to proliferate, to resist cell death, to invade, to reprogram glucose metabolism and to metastasize, the attributes that are considered important hallmarks of cancer. Therefore, inhibiting TG2 may offer a novel therapeutic approach for managing and treatment of metastatic cancer. Strategies to inhibit TG2-regulated pathways will also be discussed.

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Acknowledgments

The authors wish to thank all the students and trainees from the laboratory whose work is discussed in this review. We regret failure to include many published studies due to space constraints.

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  1. Kapil Mehta

    Present address: MolQ Personalized Medicine, 4505 Maple Street, Bellaire, TX, 77401, USA

  2. Navneet Agnihotri

    Present address: Department of Biochemistry, Panjab University, Sector 14, Chandigarh, 110 014, India

Authors and Affiliations

  1. Department of Experimental Therapeutics, Unit 1950, University of Texas MD Anderson Cancer Center, 1901 East Road, Houston, TX, 77054, USA

    Navneet Agnihotri & Kapil Mehta

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  1. Navneet Agnihotri
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Correspondence to Navneet Agnihotri or Kapil Mehta.

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The authors declare that they have no conflict of interest. One of the authors (KM) serves as a Scientific Adviser for Lifecare Innovations (India) and as Board member of MolQ Diagnostics (India) without any compensation.

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Handling Editors: S. Beninati, M. Piacentini, C. M. Bergamini.

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Agnihotri, N., Mehta, K. Transglutaminase-2: evolution from pedestrian protein to a promising therapeutic target. Amino Acids 49, 425–439 (2017). https://doi.org/10.1007/s00726-016-2320-2

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