RIP1 protects melanoma cells from apoptosis induced by BRAF/MEK inhibitors.
Fu Xi LeiLei JinXiao Ying LiuFritz LaiXu Guang YanMargaret FarrellySu Tang GuoXin Han ZhaoYuan Yuan ZhangPublished in: Cell death & disease (2018)
Many recent studies have uncovered the necessary role for the receptor-interacting protein kinase 1 (RIP1) in regulating apoptosis and necrosis that cells undergo in response to various cellular stresses. However, the functional significance of RIP1 in promoting cancer cells survival remains poorly understood. Here, we report that RIP1 was upregulated and contributed to both intrinsic and acquired resistance of melanoma cells to BRAF/MEK inhibitors through activation of NF-κB. Strikingly, Snail1-mediated suppression of CYLD played a crucial role in promoting RIP1 expression upon ERK activation, particularly, in melanoma cells with acquired resistance to BRAF inhibitors. In addition, RIP1 kinase activity was not required for melanoma cells to survive BRAF/MEK inhibition as RIP1 mediated NF-κB activation through its intermediate domain. Collectively, our findings reveal that targeting RIP1 in combination with BRAF/MEK inhibitors is a potential approach in the treatment of the disease.
Keyphrases
- pi k akt
- cell cycle arrest
- signaling pathway
- protein kinase
- oxidative stress
- metastatic colorectal cancer
- induced apoptosis
- endoplasmic reticulum stress
- wild type
- cell death
- cell proliferation
- epithelial mesenchymal transition
- lps induced
- poor prognosis
- binding protein
- dna methylation
- cancer therapy
- risk assessment
- drug delivery
- tyrosine kinase
- nuclear factor
- long non coding rna
- combination therapy