The TMEFF2 tumor suppressor modulates integrin expression, RhoA activation and migration of prostate cancer cells

Abstract

Cell adhesion and migration play important roles in physiological and pathological states, including embryonic development and cancer invasion and metastasis. The type I transmembrane protein with epidermal growth factor and two follistatin motifs 2 (TMEFF2) is expressed mainly in brain and prostate and its expression is deregulated in prostate cancer. We have previously shown that TMEFF2 can function as a tumor suppressor by inhibiting cell migration and invasion of prostate cells. However, the molecular mechanisms involved in this inhibition are not clear. In this study we demonstrate that TMEFF2 affects cell adhesion and migration of prostate cancer cells and that this effect correlates with changes in integrin expression and RhoA activation. Deletion of a 13 basic-rich amino acid region in the cytoplasmic domain of TMEFF2 prevented these effects. Overexpression of TMEFF2 reduced cell attachment and migration on vitronectin and caused a concomitant decrease in RhoA activation, stress fiber formation and expression of αv, β1 and β3 integrin subunits. Conversely, TMEFF2 interference in 22Rv1 prostate cancer cells resulted in increased integrin expression. Results obtained with a double TRAMP/TMEFF2 transgenic mouse also indicated that TMEFF2 expression reduced integrin expression in the mouse prostate. In summary, the data presented here indicate an important role of TMEFF2 in regulating cell adhesion and migration that involves integrin signaling and is mediated by its cytoplasmic domain.

Analysis of TMEFF2 allografts and transgenic mouse models reveals roles in prostate regeneration and cancer

“…Inducing TMEFF2 expression after tumor formation did not significantly impede growth or result in tumor regression (not shown), suggesting that TMEFF2 may be functioning in the early stages of the allograft establishment/progression. These results are consistent with a tumor suppressor role for TMEFF2 that we have previously reported .…”

“…Based on these results we speculated that TMEFF2, by affecting one carbon metabolism, may epigenetically affect gene expression. In fact, we have observed decreased αv, β1 and β3 integrin expression in PCa and benign cell lines overexpressing TMEFF2 and in the double TMEFF2/TRAMP transgenic mouse when compared with the TRAMP mouse . Therefore, the role of TMEFF2 in prostate regeneration could be facilitated by its effect on integrin expression via its role in metabolism.…”

“…While ectopic expression or addition of the purified extracellular domain of TMEFF2 promotes neuronal cell survival [23] and growth of several cell lines [24,25], ectopic expression of full length TMEFF2 protein demonstrates anti-proliferative effects in the same cell lines [4,25,26], and suppresses tumor growth in vivo in nude mouse xenografts [26]. In addition, we have described that TMEFF2 modulates cellular invasion of benign prostate epithelial and cancer cells and that this function correlates with its ability to modulate one-carbon metabolism [25,27,28].…”

Honokiol inhibits migration of renal cell carcinoma through activation of RhoA/ROCK/MLC signaling pathway

“…based on a number of studies, upregulated RhoA is associated with tumor progression in different types of cancer (33)(34)(35) and RhoA activation promotes the migration of cervical, colon and hepatocellular carcinoma (36)(37)(38). However, significantly downregulated expression of RhoA was demonstrated in human conventional RCC compared to that in normal kidney tissues (17) and activated RhoA has specifically been shown to inhibit the migration of breast and prostate cancer (39,40). Here, we indicated that activation of RhoA/ROCK/MLC signaling by honokiol suppresses the migration of RCC (Fig.…”

TMEFF2 shedding is regulated by oxidative stress and mediated by ADAMs and transmembrane serine proteases implicated in prostate cancer

“…This interaction results in decreased levels of sarcosine (Chen et al, 2011a; Green et al, 2013), an amino acid associated with PCa progression (Sreekumar et al, 2009). Full length TMEFF2 also attenuates the migratory properties of PCa cells (Chen et al, 2014), indicating a tumour suppressor function. However, the TMEFF2‐ECD released, due to shedding, may act as a soluble growth factor.…”