Characterization of initial key steps of IL-17 receptor B oncogenic signaling for targeted therapy of pancreatic cancer

Abstract

The members of the interleukin-17 (IL-17) cytokine family and their receptors were identified decades ago. Unlike IL-17 receptor A (IL-17RA), which heterodimerizes with IL-17RB, IL-17RC, and IL-17RD and mediates proinflammatory gene expression, IL-17RB plays a distinct role in promoting tumor growth and metastasis upon stimulation with IL-17B. However, the molecular basis by which IL-17RB promotes oncogenesis is unknown. Here, we report that IL-17RB forms a homodimer and recruits mixed-lineage kinase 4 (MLK4), a dual kinase, to phosphorylate it at tyrosine-447 upon treatment with IL-17B in vitro. Higher amounts of phosphorylated IL-17RB in tumor specimens obtained from patients with pancreatic cancer correlated with worse prognosis. Phosphorylated IL-17RB recruits the ubiquitin ligase tripartite motif containing 56 to add lysine-63–linked ubiquitin chains to lysine-470 of IL-17RB, which further assembles NF-κB activator 1 (ACT1) and other factors to propagate downstream oncogenic signaling. Consequentially, IL-17RB mutants with substitution at either tyrosine-447 or lysine-470 lose their oncogenic activity. Treatment with a peptide consisting of amino acids 403 to 416 of IL-17RB blocks MLK4 binding, tyrosine-477 phosphorylation, and lysine-470 ubiquitination in vivo, thereby inhibiting tumorigenesis and metastasis and prolonging the life span of mice bearing pancreatic tumors. These results establish a clear pathway of how proximal signaling of IL-17RB occurs and provides insight into how this pathway provides a therapeutic target for pancreatic cancer.

Overexpressed pseudogene MT1L associated with tumor immune infiltrates and indicates a worse prognosis in BLCA

“…Another meaningful finding of this study was the correlation between MT1L and interleukins shown in our GSEA. Interleukin (IL)-17 is produced by a subset of T helper (Th) cells with a strong effect on immune cells and plays an essential role in cancer pathogenesis by directly or indirectly interacting with tumors [47]. Studies have confirmed that the change patterns of IL-17 expression might be associated with the infiltration of inflammatory cells, which might also contribute to the occurrence and development of BLCA [48][49][50].…”

Exploration of the System-Level Mechanisms of the Herbal Drug FDY003 for Pancreatic Cancer Treatment: A Network Pharmacological Investigation

“…The hypoxia-inducible factor-1 alpha (HIF-1 α ) pathway is a crucial regulator of cellular adaptation of PC cells to hypoxia, and its abnormal activity may induce tumorigenesis and development of PC by promoting uncontrolled survival and growth, metabolic reprogramming, desmoplasia, immune evasion, autophagy, EMT, invasion and metastasis, stem-like tumorigenicity, angiogenesis, and radioresistance and chemoresistance of PC cells [ 157 , 158 ]. The IL-17 pathway accelerates tumorigenic and metastatic potential, and its activity serves as a predictor of PC prognosis and the efficacy of anticancer agents [ 159 – 162 ]. The Janus kinase (JAK)/STAT pathway is involved in carcinogenesis, development, growth, metastatic and angiogenic behaviors, immune surveillance, growth, stemness, anoikis resistance, EMT, treatment resistance, and invasion and migration of PC cells, while its activation is related to the reduced survival of patients with PC [ 115 – 121 , 163 , 164 ].…”

LAMTOR3 is a prognostic biomarker in kidney renal clear cell carcinoma

“… 22 Recently, it was found that IL‐17RB could play a special role in promoting tumor proliferation and metastasis. 23 The calcium signaling pathway is reportedly involved in the tumor microenvironment (TME) and resistance to some anti‐cancer drugs. 24 Accordingly, we hypothesize that LAMTOR3 can suppress KIRC progression by modulating these signaling pathways.…”