Tampering with cancer chemoresistance by targeting the TGM2-IL6-autophagy regulatory network

Abstract

Macroautophagy/autophagy is a well-established process involved in maintaining cellular homeostasis, but its role in cancer is complex and even controversial. Many studies have reported a correlative relationship between increased autophagy and evolving cancer cells under stress conditions such as nutrient or oxygen deprivation; however, there has been a lack of a plausible mechanistic link to properly target the autophagy process in the context of this microenvironment. We recently unveiled a positive regulatory loop involving TGM2 (transglutaminase 2)-NFKB/NF-κB signaling, IL6 and autophagy in cancer using mantle cell lymphoma (MCL) as a model system. These pathways are functionally connected to each other, thereby promoting malignant B cell survival and leading to enhanced lymphoma progression both in mice and in patients. Disruption of this network could provide an opportunity to increase the efficacies of current therapies and to reduce MCL drug resistance.

Keywords: IL-6; NF-κB; TG2; autophagy; cancer; lymphoma; survival; therapeutic target.

Figure 1.

Interconnected network of TGM2-NFKB and IL6-STAT3 signaling and autophagy regulation in MCL. MCL cells exploit both TGM2-NFKB signaling and the cytokine IL6 to trigger a cytoprotective autophagy response, which in turn enhances TGM2-NFKB signaling and facilitates IL6 secretion, suggesting a positive feedback loop underlying the survival and drug resistance mechanisms in MCL cells. As an upstream activator of STAT3, IL6 is stimulated by either TGM2-NFKB signaling or paracrine signals from BMSCs. MCL cells elicit IL6-mediated autophagy as an important way to favor MCL progression. MCL, mantle cell lymphoma; BMSCs, bone marrow stromal cells.