Augmentation of Therapeutic Responses in Melanoma by Inhibition of IRAK-1,-4

• Published in: Cancer research (Chicago, Ill.) Ill.), 2012-12, Vol.72 (23), p.6209-6216
• Main Authors: SRIVASTAVA, Ratika, DEGUI GENG, YINGJIA LIU, LIQIN ZHENG, ZHAOYANG LI, JOSEPH, Mary Ann, MCKENNA, Colleen, BANSAL, Navneeta, OCHOA, Augusto, DAVILA, Eduardo
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic agents; Antineoplastic Combined Chemotherapy Protocols - pharmacology; Apoptosis - drug effects; Biological and medical sciences; Cell Growth Processes - drug effects; Cell Line, Tumor; Cytokines - biosynthesis; Dermatology; Disease Models, Animal; Enzyme Activation; Female; Gene Expression Profiling; Humans; Interleukin-1 Receptor-Associated Kinases - antagonists & inhibitors; Interleukin-1 Receptor-Associated Kinases - metabolism; Male; Medical sciences; Melanoma - drug therapy; Melanoma - enzymology; Melanoma - pathology; Mice; Mice, Inbred NOD; Pharmacology. Drug treatments; Phosphorylation; Protein Kinase Inhibitors - pharmacology; Signal Transduction; Toll-Like Receptors - biosynthesis; Toll-Like Receptors - metabolism; Tumors; Tumors of the skin and soft tissue. Premalignant lesions; Xenograft Model Antitumor Assays
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.can-12-0337

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.