ARMS depletion facilitates UV irradiation-induced apoptotic cell death in melanoma
Journal
Cancer Research
Journal Volume
67
Journal Issue
24
Pages
11547-11556
Date Issued
2007
Author(s)
Abstract
Tumor cells often aberrantly reexpress molecules that mediate proper embryonic development for advantageous growth or survival. Here, we report that ankyrin repeat-rich membrane spanning (ARMS), a transmembrane protein abundant in the developing and adult neural tissues, is overexpressed in melanoma, a tumor ontogenetically originating from neural crest. Immunohistochemical study of 79 melanocytic lesions showed significantly increased expression of ARMS in primary malignant melanomas (92.9%) and metastatic melanoma (60.0%) in comparison with benign nevocellular nevi (26.7%). To investigate the role of ARMS in melanoma formation, murine B16F0 melanoma cells with stable knockdown of ARMS were established by RNA interference. Downregulation of ARMS resulted in significant inhibition of anchorage-independent growth in soft agar and restrictive growth of melanoma in severe combined immunodeficient mice. Importantly, depletion of ARMS facilitated UVB-induced apoptosis in melanoma cells through inactivation of mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) kinase (MEK)/ERK. Addition of MEK inhibitor PD98059 further sensitized ARMS-depleted melanoma cells to UVB-induced apoptosis, whereas constitutively active MEK rescued ARMS-depleted cells from apoptosis. We further showed that BRAF, a downstream signaling molecule of ARMS in ERK pathway, is not mutated as a constitutively active form in acral lentiginous melanoma; in contrast, BRAFT1799A mutation, which leads to constitutive activation of ERK signaling, was detected in 57.1% of superficial spreading melanoma. Our study suggests that overexpression of ARMS per se serves as one mechanism to promote melanoma formation by preventing stress-induced apoptotic death mediated by the MEK/ERK signaling pathway, especially in acral lentiginous melanoma, most of which does not harbor BRAF mutation. ?2007 American Association for Cancer Research.
SDGs
Other Subjects
2 (2 amino 3 methoxyphenyl)chromone; ankyrin repeat rich membrane spanning protein; B Raf kinase; membrane protein; mitogen activated protein kinase; unclassified drug; animal cell; apoptosis; article; cell death; controlled study; gene mutation; gene overexpression; human; human cell; human tissue; immunohistochemistry; melanoma; mouse; nevus; nonhuman; priority journal; protein expression; RNA interference; skin carcinogenesis; ultraviolet B radiation; ultraviolet irradiation; Animals; Apoptosis; Cell Line, Tumor; Foreskin; Humans; Infant, Newborn; Male; Melanocytes; Melanoma; Membrane Proteins; Mice; Mice, SCID; Mutation; Nerve Tissue Proteins; Proto-Oncogene Proteins B-raf; Reverse Transcriptase Polymerase Chain Reaction; RNA Interference; Transfection; Ultraviolet Rays
Type
journal article