The transglutaminase 2 cancer cell survival factor maintains mTOR activity to drive an aggressive cancer phenotype

Abstract

Transglutaminase 2 (TG2) is an important cancer stem-like cell survival protein that is highly expressed in epidermal squamous cell carcinoma and drives an aggressive cancer phenotype. In the present study, we show that TG2 knockdown or inactivation results in a reduction in mammalian target of rapamycin (mTOR) level and activity in epidermal cancer stem-like cells which are associated with reduced spheroid formation, invasion, and migration, and reduced cancer stem cell and epithelial-mesenchymal transition (EMT) marker expression. Similar changes were observed in both cultured cells and tumors. mTOR knockdown or treatment with rapamycin phenocopies the reduction in spheroid formation, invasion, and migration, and cancer stem cell and EMT marker expression. Moreover, mTOR appears to be a necessary mediator of TG2 action, as a forced expression of constitutively active mTOR in TG2 knockdown cells partially restores the aggressive cancer phenotype and cancer stem cell and EMT marker expression. Tumor studies show that rapamycin reduces tumor growth and cancer stem cell marker expression and EMT.These studies suggest that TG2 stimulates mTOR activity to stimulate cancer cell stemness and EMT and drive aggressive tumor growth.cancer stem cells, epidermal squamous cell carcinoma, mTOR, transglutaminase 2 | INTRODUCTIONTransglutaminase 2 (TG2) is a uniquely oncogenic member of the transglutaminase family that is a focus of intense study relating to its role as a cancer cell survival factor. 1,2 TG2 displays transamidase and GTP binding activity, and recent studies show that GTP binding activity is required to maintain the cancer phenotype. 1-4 TG2 level and signaling activity are markedly increased in tumors and tumor cell lines [5][6][7][8][9] where it suppresses expression of tumor suppressor genes, drives synthesis, and deposition of fibronectin and collagen, stabilizes the extracellular matrix and stimulates epithelial-mesenchymal transition (EMT). 4,9,10 Recent studies indicate that TG2 is highly enriched in epidermal cancer stem-like cells (ECS cells) where it stimulates an aggressive cancer phenotype. [2][3][4]11 It localizes in the extra-and intracellular environment where it regulates a host of procancer plasma membrane receptors and intracellular signaling cascades. 3,[11][12][13][14][15] Mammalian target of rapamycin complex 1 (mTORC1) and mTORC2 comprise two distinct functional complexes. mTORC1 (mammalian target of rapamycin [mTOR]) is involved in driving the survival of cancer cells. 16 mTOR is activated in response to nutrient conditions favorable for cell growth and in response to signaling

Sulforaphane inhibits CD44v6/YAP1/TEAD signaling to suppress the cancer phenotype

“…The two‐tailed the Student's t test was used for binary comparison between control and experimental groups. All experiments were repeated three times and the data is presented as mean ± SEM 32 …”

Targeting transglutaminase 2 mediated exostosin glycosyltransferase 1 signaling in liver cancer stem cells with acyclic retinoid

“…Although TG2 is well-known for its function in the maintenance of CSC-like cell survival in diverse cancers such as breast cancer [ 38 ], epidermal squamous cell carcinoma [ 39 ], renal cell carcinoma [ 40 ], ovarian cancer [ 41 ], and colon cancer [ 42 ], little is known about its role in liver CSCs [ 43 ]. In contrast, two independent clinical studies showed that the tissue and/or serum TG2 expression were significantly increased in patients with early stage HCC whose with no evaluated level of AFP [ 44 ] or with early recurrence within 12 months after primary treatment [ 45 ].…”