Autocrine/Paracrine Secreted Frizzled-related Protein 2 Induces Cellular Resistance to Apoptosis

Abstract

Abnormal regulation of apoptosis and cell proliferation is thought to be involved in tumor formation. The secreted Frizzled-related protein 2 (SFRP2) was detected in primary culture of canine mammary gland tumors but not in normal mammary tissues. Thus, to elucidate the role of SFRP2 in mammary tumorigenesis, we overexpressed SFRP2 in mammary gland tumor and MCF7 cells. The results indicated that SFRP2 is secreted and incorporated into the extracellular matrix (ECM) of the tumor and normal cells. In an attempt to understand the molecular basis underlying the interaction between SFRP2 and ECM, co-immunoprecipitation and cell adhesion assays were carried out. SFRP2 was found to be associated with the fibronectin-integrin protein complex and could promote cell adhesion. DNA fragmentation and caspase 3 activity analyses showed that the susceptibility of the cells to UV-induced apoptosis decreased in the context of SFRP2 overexpression. Upon disruption of the fibronectin-integrin connection, the antiapoptosis activity of SFRP2 was decreased. Moreover, SFRP2 was found to induce tumorous transformation in normal mammary epithelial cells and to inhibit apoptosis in a modified paracrine model. Collectively, our results emphasize the relevance of SFRP2 and ECM in mammary tumorigenesis and provide further insight into the mechanism of SFRP2 action.

Secreted frizzled related proteins: Implications in cancers

“…associated with the fibronectin-integrin protein complex in the extracellular matrix (ECM) to mediate cell adhesion, and disruption of the same complex abrogated the anti-apoptotic activity of SFRP2 [68]. The same group also characterized the activation of NFкB or the supppression of c-Jun Nterminal kinase (JNK) as being behind the anti-apoptotic role of SFRP2 [69].…”

Cyclin T1 overexpression induces malignant transformation and tumor growth

“…12,36,37 A deregulation in the antiapoptotic CDK9-signaling system may lead to malignant cell transformation, as reported in a number of other systems, such as insulin-like growth factor-I receptor, epidermal growth factor receptor, autocrine/ paracrine secreted Frizzled-related protein 2, AKTrelated pathway and surviving. [38][39][40][41] A deregulated CDK9-related pathway was observed in several human tumors: lymphomas, 14,30,42 neuroblastoma, 17 primary neuroectodermal tumor (PNET), 17 rhabdomyosarcoma 31 and prostate cancer. 32 For instance, an imbalance in CDK9 and Cyclin T1 mRNA was observed in several hematopoietic malignancies: follicular lymphoma, diffuse large B-cell lymphoma with germinal center phenotype, Burkitt's lymphoma and cell lines of classical Hodgkin's lymphoma.…”

Mass Spectrometry–based Proteomic Analysis of the Matrix Microenvironment in Pluripotent Stem Cell Culture

“…Additionally, sFRP2 was identified as potentially regulated by Nanog in ChIP analyses of hESCs (46). The C-terminal netrin domain on sFRP1 and sFRP2 is known to confer heparin-binding properties that potentially regulate the activity of the parent protein (47,48). Lefty A and B regulate TGF-␤ signaling through antagonism of the activating protein Nodal (49).…”