Targeting the Primordial Chaperone to Overcome Acquired Drug Resistance in Cancer: TG2-Mediated Autophagy
Year: 2025
Type: article
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.
Source: Biomolecules & Therapeutics
Author: Soo-Youl Kim
Institution: National Cancer Center
Language: English
Subfield: Epidemiology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Funder: National Cancer Center
Award: G8211469303
OpenAlex ID: W7119119814