RIP1 Kinase Is an Oncogenic Driver in Melanoma.
Although many studies have uncovered an important role for the receptor-binding protein kinase RIP1 in controlling cell death signaling, its possible contributions to cancer pathogenesis have been little explored. Here, we report that RIP1 functions as an oncogenic driver in human melanoma. Although RIP1 was commonly upregulated in melanoma, RIP1 silencing inhibited melanoma cell proliferation in vitro and retarded the growth of melanoma xenografts in vivo. Conversely, while inducing apoptosis in a small proportion of melanoma cells, RIP1 overexpression enhanced proliferation in the remaining cells. Mechanistic investigations revealed that the proliferative effects of RIP1 overexpression were mediated by NF-κB activation. Strikingly, ectopic expression of RIP1 enhanced the proliferation of primary melanocytes, triggering their anchorage-independent cell growth in an NF-κB-dependent manner. We identified DNA copy-number gain and constitutive ubiquitination by a TNFα autocrine loop mechanism as two mechanisms of RIP1 upregulation in human melanomas. Collectively, our findings define RIP1 as an oncogenic driver in melanoma, with potential implications for targeting its NF-κB-dependent activation mechanism as a novel approach to treat this disease.
School of Medicine and Public Health, The University of Newcastle, New South Wales, Australia. School of Life Science, Anhui Medical University, Anhui, China.
Xiao Ying
XY
Liu
School of Medicine and Public Health, The University of Newcastle, New South Wales, Australia.
Fritz
F
Lai
School of Medicine and Public Health, The University of Newcastle, New South Wales, Australia.
Xu Guang
XG
Yan
School of Medicine and Public Health, The University of Newcastle, New South Wales, Australia.
Chen Chen
CC
Jiang
School of Medicine and Public Health, The University of Newcastle, New South Wales, Australia. Department of Molecular Biology, Shanxi Cancer Hospital and Institute, Shanxi, China.
Su Tang
ST
Guo
School of Medicine and Public Health, The University of Newcastle, New South Wales, Australia. Department of Molecular Biology, Shanxi Cancer Hospital and Institute, Shanxi, China.
Chun Yan
CY
Wang
School of Medicine and Public Health, The University of Newcastle, New South Wales, Australia.
Amanda
A
Croft
School of Medicine and Public Health, The University of Newcastle, New South Wales, Australia.
Hsin-Yi
HY
Tseng
Discipline of Pathology, The University of Sydney, and Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia.
James S
JS
Wilmott
Discipline of Pathology, The University of Sydney, and Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia.
Richard A
RA
Scolyer
School of Medicine and Public Health, The University of Newcastle, New South Wales, Australia. Xu.Zhang@newcastle.edu.au Lei.Jin@newcastle.edu.au.
Lei
L
Jin
School of Medicine and Public Health, The University of Newcastle, New South Wales, Australia. Xu.Zhang@newcastle.edu.au Lei.Jin@newcastle.edu.au.
Xu Dong
XD
Zhang
D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D002478:Cells, Cultured; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008297:Male; D008544:Melanocytes / Q000378:metabolism / Q000473:pathology; D008545:Melanoma / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D009857:Oncogenes; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000494:pharmacology; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D012878:Skin Neoplasms / Q000235:genetics* / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
D016328:NF-kappa B; D034741:RNA, Small Interfering; D053422:Receptor-Interacting Protein Serine-Threonine Kinases