Targeting the Primordial Chaperone to Overcome Acquired Drug Resistance in Cancer: TG2-Mediated Autophagy
10.4062/biomolther.2025.247
- Author:
Soo-Youl KIM
1
Author Information
1. Division of Cancer Biology, Research Institute, National Cancer Center; New Cancer Cure-Bio Co., Goyang 10408, Republic of Korea
- Publication Type:Invited Review
- From:Biomolecules & Therapeutics
2026;34(1):6-17
- CountryRepublic of Korea
- Language:English
-
Abstract:
The transglutaminase family is roughly 250 million years old. Horseshoe crabs have been described as a ‘living fossil’ and have remained virtually unchanged since first appearing around the Triassic period. The horseshoe crab, a living fossil, carries a primitive form of TG that helps it defend against infection and survive. Transglutaminase 2 (TG2, EC 2.3.2.13, gene name TGM2) is mainly known as a cross-linking enzyme in vertebrates. Although TG2 is not an oncogene, its high levels are linked to worse outcomes in many cancers. However, how TG2 cross-linking activity relates to its role in promoting cancer growth remains unclear. A recent discovery sheds light on this. In ovarian cancer cells, TG2 binds directly to GSK3β, leading to its removal by autophagosomes, which activates β-catenin. Stopping this interaction allows GSK3β levels to recover, thereby decreasing β-catenin activity. Even in the absence of cross-linking, cancer cells use TG2 as a chaperone to promote growth and support metastasis. This suggests intracellular calcium levels are too low for TG2 to perform cross-linking. It also indicates that anticancer treatments may increase TG2 levels in cancer cells, helping them recover by removing tumor suppressors. As a result, TG2 plays a role in developing drug resistance, acting as a primitive systemic defense mechanism linked with survival signals. I suggest that blocking TG2 binding, combined with inhibiting autophagy or alternative signaling pathways, is essential for effectively overcoming drug resistance, since it is rooted in TG2’s primordial role.
