Abstract
Semaphorin 6A (SEMA6A), a membrane-bound protein, is downregulated in lung cancer tissue compared to its adjacent normal tissue. However, the functions of SEMA6A in lung cancer cells are still unclear. In the present study, full length SEMA6A and various truncations were transfected into lung cancer cells to investigate the role of the different domains of SEMA6A in cell proliferation and survival, apoptosis, and in vivo tumor growth. SEMA6A-induced cell signaling was explored using gene silencing, co-immunoprecipitation, and co-culture assays. Our results showed that overexpression of SEMA6A reduced the growth of lung cancer cells in vitro and in vivo, and silencing SEMA6A increased the proliferation of normal lung fibroblasts. Truncated SEMA6A lacking the SEMA domain or the extracellular region induced more apoptosis than full length SEMA6A, and reintroducing the SEMA domain attenuated the apoptosis. Fas-associated protein with death domain (FADD) bound to the cytosolic region of truncated SEMA6A and was involved in SEMA6A-associated cytosol-induced apoptosis. This study suggests a novel function of SEMA6A in inducing apoptosis via FADD binding in lung cancer cells.
Highlights
Dysregulation of apoptotic pathways can lead to tumorigenesis through transformation of normal cells to malignant cells[1]
Semaphorin 6A (SEMA6A) decreases the growth of lung cancer cells Given the low expression of SEMA6A in lung cancer cells, we studied the effects of SEMA6A overexpression on cell proliferation, colony formation, and apoptosis in A549 and H1299 cells
Our study has provided solid evidence supporting a novel role of SEMA6A in apoptosis, which can inhibit the growth of lung cancer cells in vitro and in vivo and is regulated by the integral SEMA domain
Summary
Dysregulation of apoptotic pathways can lead to tumorigenesis through transformation of normal cells to malignant cells[1]. The apoptotic pathways are initiated by death receptors (DRs) on the cell membrane. DRs are triggered by their extracellular ligands, molecules such as Fas-associated protein with death domain (FADD) or tumor necrosis factor receptor type 1-associated death domain (TRADD) are recruited to the cytosolic region of the DRs and subsequently activate the downstream death signaling[2]. Inactivation of DRs by mutations shows a high association with some types of cancer, suggesting the importance of DRs in tumorigenesis[3]. Other membrane proteins like the semaphorin family may participate in regulation of apoptotic signaling[4,5]
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