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An integrative proteomics approach identifies tyrosine kinase KIT as a therapeutic target for SPINK1-positive prostate cancer.

ABSTRACT: Elevated serine peptidase inhibitor, Kazal type 1 (SPINK1) levels in ∼10%-25% of prostate cancer (PCa) patients associate with aggressive phenotype, for which there are limited treatment choices and dismal clinical outcomes. Using an integrative proteomics approach involving label-free phosphoproteome and proteome profiling, we delineated the downstream signaling pathways involved in SPINK1-mediated tumorigenesis and identified tyrosine kinase KIT as highly enriched. Furthermore, high to moderate levels of KIT expression were detected in ∼85% of SPINK1-positive PCa specimens. We show KIT signaling orchestrates SPINK1-mediated oncogenesis, and treatment with KIT inhibitor reduces tumor growth and metastases in preclinical mice models. Mechanistically, KIT signaling modulates WNT/β-catenin pathway and confers stemness-related features in PCa. Notably, inhibiting KIT signaling led to restoration of AR/REST levels, forming a feedback loop enabling SPINK1 repression. Overall, we uncover the role of KIT signaling downstream of SPINK1 in maintaining lineage plasticity and provide distinct treatment modalities for advanced-stage SPINK1-positive patients.

SUBMITTER: Manzar N

PROVIDER: S-EPMC10879682 | biostudies-literature | 2024 Mar

REPOSITORIES: biostudies-literature

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An integrative proteomics approach identifies tyrosine kinase KIT as a therapeutic target for SPINK1-positive prostate cancer.

Manzar Nishat N Khan Umar Khalid UK Goel Ayush A Carskadon Shannon S Gupta Nilesh N Palanisamy Nallasivam N Ateeq Bushra B

iScience 20240104 3

Elevated serine peptidase inhibitor, Kazal type 1 (SPINK1) levels in ∼10%-25% of prostate cancer (PCa) patients associate with aggressive phenotype, for which there are limited treatment choices and dismal clinical outcomes. Using an integrative proteomics approach involving label-free phosphoproteome and proteome profiling, we delineated the downstream signaling pathways involved in SPINK1-mediated tumorigenesis and identified tyrosine kinase KIT as highly enriched. Furthermore, high to moderat ...[more]

PMID: 38384854

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Project description:PurposeSerine peptidase inhibitor, Kazal type-1 (SPINK1) overexpression defines the second most recurrent and aggressive prostate cancer subtype. However, the underlying molecular mechanism and pathobiology of SPINK1 in prostate cancer remains largely unknown.Experimental designmiRNA prediction tools were employed to examine the SPINK1-3'UTR for miRNA binding. Luciferase reporter assays were performed to confirm the SPINK1-3'UTR binding of shortlisted miR-338-5p/miR-421. Furthermore, miR-338-5p/-421-overexpressing cancer cells (SPINK1-positive) were evaluated for oncogenic properties using cell-based functional assays and a mouse xenograft model. Global gene expression profiling was performed to unravel the biological pathways altered by miR-338-5p/-421. IHC and RNA in situ hybridization were carried out on prostate cancer patients' tissue microarray for SPINK1 and EZH2 expression, respectively. Chromatin immunoprecipitation assay was performed to examine EZH2 occupancy on the miR-338-5p/-421-regulatory regions. Bisulfite sequencing and methylated DNA immunoprecipitation were performed on prostate cancer cell lines and patients' specimens.ResultsWe established a critical role of miRNA-338-5p/-421 in posttranscriptional regulation of SPINK1. Ectopic expression of miRNA-338-5p/-421 in SPINK1-positive cells abrogates oncogenic properties including cell-cycle progression, stemness, and drug resistance, and shows reduced tumor burden and distant metastases in a mouse model. Importantly, we show that patients with SPINK1-positive prostate cancer exhibit increased EZH2 expression, suggesting its role in epigenetic silencing of miRNA-338-5p/-421. Furthermore, presence of CpG dinucleotide DNA methylation marks on the regulatory regions of miR-338-5p/-421 in SPINK1-positive prostate cancer cells and patients' specimens confirms epigenetic silencing.ConclusionsOur findings revealed that miRNA-338-5p/-421 are epigenetically silenced in SPINK1-positive prostate cancer, although restoring the expression of these miRNAs using epigenetic drugs or synthetic mimics could abrogate SPINK1-mediated oncogenesis.See related commentary by Bjartell, p. 2679.

Project description:BackgroundLaryngeal cancer (LC) is a prevalent head and neck malignancy; however, the essential pathophysiological mechanism underlying its tumorigenesis and progression remains elusive. Due to the perduring scarcity of effective targeted drugs for laryngeal cancer, insights into the disease's pathophysiological mechanisms would substantially impact the treatment landscape of laryngeal cancer.MethodsTo ensure quality consistency, 10 tumor and 9 non-tumor samples underwent proteomic analysis on a single mass spectrometer using a label-free technique. Subsequently, gene expression variations between laryngeal squamous cell carcinoma and normal tissues were analyzed using The Cancer Genome Atlas (TCGA) database. Immunohistochemical expressions of insulin-like growth factor 2 receptor (IGF2R), fibronectin (FN), vimentin, and α-smooth muscle actin (SMA) in LC tissues and normal tissues were determined.ResultsIn the tumor group, significant variations were detected for 433 upregulated and 61 downregulated proteins. Moreover, the heatmap revealed that the expressions of RNA translation-related proteins and proteins involved in RNA metabolism, such as IGF2R, tenascin C (TNC), periostin (POSTN), proteasome 26S subunit ATPase 4 (PSMC4), serpin family A member 3 (SERPINA3), heat shock protein family B (small) member 6 (HSPB6), osteoglycin (OGN), chaperonin containing TCP1 subunit 6A (CCT6A), and chaperonin containing TCP1 subunit 6B (CCT6B), were prominently elevated in the tumor group. Nonsense-mediated RNA decay (NMD), RNA translation, and protein stability were significantly altered in LC tumors. IGF2R was remarkably upregulated in LC tumors. In the TCGA database, the IGF2R mRNA level was significantly upregulated in LSCC tissues. Additionally, IGF2R mRNA expression was lowest in clinical grade 1 samples, with no significant difference between grades 2 and 3. In LSCC patients, a significant positive correlation between IGF2R expression and the stromal score was detected using the ESTIMATE algorithm to estimate the immune score, stromal score, and tumor purity in the tumor microenvironment. Lastly, immunohistochemical analysis revealed that IGF2R is overexpressed in LC.ConclusionThese results demonstrate the vital role of IGF2R in LC carcinogenesis and progression and may facilitate the identification of new therapeutic targets for the prevention and treatment of LC.

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An integrative proteomics approach identifies tyrosine kinase KIT as a therapeutic target for SPINK1-positive prostate cancer.

Publications

An integrative proteomics approach identifies tyrosine kinase KIT as a therapeutic target for SPINK1-positive prostate cancer.

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