title: Augmentation of therapeutic responses in melanoma by inhibition of IRAK-1,-4.
abstract: Toll-like receptors (TLR) are expressed by a variety of cancers, including melanoma, but their functional contributions in cancer cells are uncertain. To approach this question, we evaluated the effects of stimulating or inhibiting the TLR/IL-1 receptor-associated kinases IRAK-1 and IRAK-4 in melanoma cells where their functions are largely unexplored. TLRs and TLR-related proteins were variably expressed in melanoma cell lines, with 42% expressing activated phospho-IRAK-1 constitutively and 85% expressing high levels of phospho-IRAK-4 in the absence of TLR stimulation. Immunohistochemical evaluation of melanoma tumor biopsies (n = 242) revealed two distinct patient populations, one that expressed p-IRAK-4 levels similar to normal skin (55%) and one with significantly higher levels than normal skin (45%). Levels of p-IRAK-4 levels did not correlate with clinical stage, gender, or age, but attenuated IRAK-1,-4 signaling with pharmacologic inhibitors or siRNA-enhanced cell death in vitro in combination with vinblastine. Moreover, in a xenograft mouse model of melanoma, the combined pharmacologic treatment delayed tumor growth and prolonged survival compared with subjects receiving single agent therapy. We propose p-IRAK-4 as a novel inflammation and prosurvival marker in melanoma with the potential to serve as a therapeutic target to enhance chemotherapeutic responses.
authors.affiliation: Marlene and Stewart Greenebaum NCI Cancer Center, University of Maryland, Baltimore, MD 21201-1559, USA.
authors.forename: Ratika
authors.initials: R
authors.lastname: Srivastava
authors.forename: Degui
authors.initials: D
authors.lastname: Geng
authors.forename: Yingjia
authors.initials: Y
authors.lastname: Liu
authors.forename: Liqin
authors.initials: L
authors.lastname: Zheng
authors.forename: Zhaoyang
authors.initials: Z
authors.lastname: Li
authors.forename: Mary Ann
authors.initials: MA
authors.lastname: Joseph
authors.forename: Colleen
authors.initials: C
authors.lastname: McKenna
authors.forename: Navneeta
authors.initials: N
authors.lastname: Bansal
authors.forename: Augusto
authors.initials: A
authors.lastname: Ochoa
authors.forename: Eduardo
authors.initials: E
authors.lastname: Davila
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D016207:Cytokines / Q000096:biosynthesis; D004195:Disease Models, Animal; D004789:Enzyme Activation; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D053592:Interleukin-1 Receptor-Associated Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D051379:Mice; D016688:Mice, Inbred NOD; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D015398:Signal Transduction; D051193:Toll-Like Receptors / Q000096:biosynthesis / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D016207:Cytokines; D047428:Protein Kinase Inhibitors; D051193:Toll-Like Receptors; C507768:IRAK1 protein, human; C507773:IRAK4 protein, human; D053592:Interleukin-1 Receptor-Associated Kinases