Evidence for 2-Methoxyestradiol-Mediated Inhibition of Receptor Tyrosine Kinase RON in the Management of Prostate Cancer

2-Methoxyestradiol (2-ME2) possesses anti-tumorigenic activities in multiple tumor models with acceptable tolerability profile in humans. Incomplete understanding of the mechanism has hindered its development as an anti-tumorigenic compound. We have identified for the first-time macrophage stimulatory protein 1 receptor (MST1R) as a potential target of 2-ME2 in prostate cancer cells. Human tissue validation studies show that MST1R (a.k.a RON) protein levels are significantly elevated in prostate cancer tissues compared to adjacent normal/benign glands. Serum levels of macrophage stimulatory protein (MSP), a ligand for RON, is not only associated with the risk of disease recurrence, but also significantly elevated in samples from African American patients. 2-ME2 treatment inhibited mechanical properties such as adhesion and elasticity that are associated with epithelial mesenchymal transition by downregulating mRNA expression and protein levels of MST1R in prostate cancer cell lines. Intervention with 2-ME2 significantly reduced tumor burden in mice. Notably, global metabolomic profiling studies identified significantly higher circulating levels of bile acids in castrated animals that were decreased with 2-ME2 intervention. In summary, findings presented in this manuscript identified MSP as a potential marker for predicting biochemical recurrence and suggest repurposing 2-ME2 to target RON signaling may be a potential therapeutic modality for prostate cancer.

[1]  S. Waltz,et al.  Prostate Epithelial RON Signaling Promotes M2 Macrophage Activation to Drive Prostate Tumor Growth and Progression , 2020, Molecular Cancer Research.

[2]  V. Takiar,et al.  MST1R (RON) expression is a novel prognostic biomarker for metastatic progression in breast cancer patients , 2020, Breast Cancer Research and Treatment.

[3]  D. Ribatti,et al.  Epithelial-Mesenchymal Transition in Cancer: A Historical Overview , 2020, Translational oncology.

[4]  T. Becker,et al.  The Prospect of Identifying Resistance Mechanisms for Castrate-Resistant Prostate Cancer Using Circulating Tumor Cells: Is Epithelial-to-Mesenchymal Transition a Key Player? , 2020, Prostate cancer.

[5]  Y. Duan,et al.  Advance of 2-methoxyestradiol as a promising anticancer agent for cancer therapy. , 2020, Future medicinal chemistry.

[6]  A. Jemal,et al.  Cancer statistics, 2020 , 2020, CA: a cancer journal for clinicians.

[7]  Ke-Guang Cheng,et al.  Design, Synthesis, and Evaluation of Novel 2-Methoxyestradiol Derivatives as Apoptotic Inducers through an Intrinsic Apoptosis Pathway , 2020, Biomolecules.

[8]  Addanki P. Kumar,et al.  Receptor tyrosine kinase recepteur d'origine nantais as predictive marker for aggressive prostate cancer in African Americans , 2019, Molecular carcinogenesis.

[9]  J. Strauss,et al.  Molecular modelling predicts that 2-methoxyestradiol disrupts HIF function by binding to the PAS-B domain , 2019, Steroids.

[10]  Joshua M. Korn,et al.  Next-generation characterization of the Cancer Cell Line Encyclopedia , 2019, Nature.

[11]  Yaqing Chang,et al.  Directly observing alterations of morphology and mechanical properties of living cancer cells with atomic force microscopy. , 2019, Talanta.

[12]  G. Swanson,et al.  Suppression of ribosomal protein RPS6KB1 by Nexrutine increases sensitivity of prostate tumors to radiation. , 2018, Cancer letters.

[13]  Xingyong Chen,et al.  Inhibition of immunoproteasome promotes angiogenesis via enhancing hypoxia-inducible factor-1α abundance in rats following focal cerebral ischaemia , 2018, Brain, Behavior, and Immunity.

[14]  K. Komurov,et al.  Tumor Cell Autonomous RON Receptor Expression Promotes Prostate Cancer Growth Under Conditions of Androgen Deprivation12 , 2018, Neoplasia.

[15]  S. Bhattacharyya,et al.  Epithelial to mesenchymal transition induces stem cell like phenotype in renal cell carcinoma cells , 2018, Cancer Cell International.

[16]  Peter W. Laird,et al.  Cell-of-Origin Patterns Dominate the Molecular Classification of 10,000 Tumors from 33 Types of Cancer , 2018, Cell.

[17]  S. Eggener,et al.  African-American Prostate Cancer Disparities , 2017, Current Urology Reports.

[18]  A. Satelli,et al.  EMT circulating tumor cells detected by cell-surface vimentin are associated with prostate cancer progression , 2017, Oncotarget.

[19]  H. Yao,et al.  RON and c-Met facilitate metastasis through the ERK signaling pathway in prostate cancer cells , 2017, Oncology reports.

[20]  D. Albanes,et al.  Prospective serum metabolomic profile of prostate cancer by size and extent of primary tumor , 2017, Oncotarget.

[21]  R. Salgia,et al.  The receptor tyrosine kinase AXL mediates nuclear translocation of the epidermal growth factor receptor , 2017, Science Signaling.

[22]  David C. Smith,et al.  Phase II randomised discontinuation trial of cabozantinib in patients with advanced solid tumours. , 2017, European journal of cancer.

[23]  A. Ingram,et al.  Nuclear transportation of exogenous epidermal growth factor receptor and androgen receptor via extracellular vesicles. , 2017, European journal of cancer.

[24]  E. Schaeffer,et al.  Increasing incidence of metastatic prostate cancer in the United States (2004–2013) , 2016, Prostate Cancer and Prostatic Diseases.

[25]  T. Huang,et al.  Crosstalk between RON and androgen receptor signaling in the development of castration resistant prostate cancer , 2016, Oncotarget.

[26]  J. Moul,et al.  Prostate cancer in men of African origin , 2016, Nature Reviews Urology.

[27]  David C. Smith,et al.  Mechanistic Support for Combined MET and AR Blockade in Castration-Resistant Prostate Cancer , 2016, Neoplasia.

[28]  Huiyoung Yun,et al.  Recepteur d'origine nantais (RON), more than a kinase: Role in castrate‐resistant prostate cancer , 2015, Molecular carcinogenesis.

[29]  Jie Li,et al.  2-Methoxyestradiol synergizes with sorafenib to suppress hepatocellular carcinoma by simultaneously dysregulating hypoxia-inducible factor-1 and -2. , 2014, Cancer letters.

[30]  M. Lai,et al.  Hypoxia promotes nuclear translocation and transcriptional function in the oncogenic tyrosine kinase RON. , 2014, Cancer research.

[31]  M. Gleave,et al.  Crosstalk between nuclear MET and SOX9/β-catenin correlates with castration-resistant prostate cancer. , 2014, Molecular endocrinology.

[32]  S. Waltz,et al.  Hepatocyte growth factor-like protein is required for prostate tumor growth in the TRAMP mouse model , 2014, Oncotarget.

[33]  Howard I. Scher,et al.  High-risk prostate cancer—classification and therapy , 2014, Nature Reviews Clinical Oncology.

[34]  M. Hung,et al.  Syntaxin 6-mediated Golgi translocation plays an important role in nuclear functions of EGFR through microtubule-dependent trafficking , 2014, Oncogene.

[35]  S. Zhao,et al.  Knockdown of RON receptor kinase delays but does not prevent tumor progression while enhancing HGF/MET signaling in pancreatic cancer cell lines , 2013, Oncogenesis.

[36]  Ruiwen Zhang,et al.  MSP–RON signalling in cancer: pathogenesis and therapeutic potential , 2013, Nature Reviews Cancer.

[37]  Benjamin E. Gross,et al.  Integrative Analysis of Complex Cancer Genomics and Clinical Profiles Using the cBioPortal , 2013, Science Signaling.

[38]  S. Kambhampati,et al.  A Second-Generation 2-Methoxyestradiol Prodrug Is Effective against Barrett's Adenocarcinoma in a Mouse Xenograft Model , 2013, Molecular Cancer Therapeutics.

[39]  D. Wheeler,et al.  Yes and Lyn play a role in nuclear translocation of the Epidermal Growth Factor Receptor , 2012, Oncogene.

[40]  Addanki P. Kumar,et al.  Dietary Resveratrol Prevents Development of High-Grade Prostatic Intraepithelial Neoplastic Lesions: Involvement of SIRT1/S6K Axis , 2012, Cancer Prevention Research.

[41]  Edward D. Karoly,et al.  Prospective Study of Changes in the Metabolomic Profiles of Men during Their First Three Months of Androgen Deprivation Therapy for Prostate Cancer , 2012, Clinical Cancer Research.

[42]  Benjamin E. Gross,et al.  The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. , 2012, Cancer discovery.

[43]  S. Waltz,et al.  Ron receptor overexpression in the murine prostate induces prostate intraepithelial neoplasia. , 2012, Cancer letters.

[44]  M. Henry,et al.  Epithelial-to-mesenchymal transition in prostate cancer: paradigm or puzzle? , 2011, Nature Reviews Urology.

[45]  A. Lentsch,et al.  THE RON RECEPTOR PROMOTES PROSTATE TUMOR GROWTH IN THE TRAMP MOUSE MODEL , 2011, Oncogene.

[46]  D. Hanahan,et al.  Hallmarks of Cancer: The Next Generation , 2011, Cell.

[47]  A. Mueck,et al.  2-Methoxyestradiol—Biology and mechanism of action , 2010, Steroids.

[48]  Chung-Liang Ho,et al.  An unusual function of RON receptor tyrosine kinase as a transcriptional regulator in cooperation with EGFR in human cancer cells. , 2010, Carcinogenesis.

[49]  S. Waltz,et al.  THE RON RECEPTOR TYROSINE KINASE POSITIVELY REGULATES ANGIOGENIC CHEMOKINE PRODUCTION IN PROSTATE CANCER CELLS , 2009, Oncogene.

[50]  Corey D. DeHaven,et al.  Integrated, nontargeted ultrahigh performance liquid chromatography/electrospray ionization tandem mass spectrometry platform for the identification and relative quantification of the small-molecule complement of biological systems. , 2009, Analytical chemistry.

[51]  S. Ammanamanchi,et al.  Recepteur d'Origine Nantais Tyrosine Kinase Is a Direct Target of Hypoxia-inducible Factor-1α-mediated Invasion of Breast Carcinoma Cells* , 2009, Journal of Biological Chemistry.

[52]  Abraham Nyska,et al.  Discovery of Metabolomics Biomarkers for Early Detection of Nephrotoxicity , 2009, Toxicologic pathology.

[53]  M. Hung,et al.  Nuclear EGFR is required for cisplatin resistance and DNA repair. , 2009, American journal of translational research.

[54]  D. Troyer,et al.  Involvement of FLIP in 2-Methoxyestradiol–Induced Tumor Regression in Transgenic Adenocarcinoma of Mouse Prostate Model , 2009, Clinical Cancer Research.

[55]  G. Wilding,et al.  Phase I Trial of 2-Methoxyestradiol NanoCrystal Dispersion in Advanced Solid Malignancies , 2009, Clinical Cancer Research.

[56]  James K. Gimzewski,et al.  Applicability of AFM in cancer detection , 2009 .

[57]  John T. Wei,et al.  Metabolomic profiles delineate potential role for sarcosine in prostate cancer progression , 2009, Nature.

[58]  Addanki P. Kumar,et al.  Combination of 2-methoxyestradiol (2-ME2) and eugenol for apoptosis induction synergistically in androgen independent prostate cancer cells , 2009, The Journal of Steroid Biochemistry and Molecular Biology.

[59]  M. Lekka,et al.  Biomedical applications of AFM , 2009 .

[60]  M. Milburn,et al.  Analysis of the adult human plasma metabolome. , 2008, Pharmacogenomics.

[61]  S. Kambhampati,et al.  2‐Methoxyestradiol modulates β‐catenin in prostate cancer cells: A possible mediator of 2‐methoxyestradiol‐induced inhibition of cell growth , 2008, International journal of cancer.

[62]  T. Slaga,et al.  2-Methoxyestradiol Inhibits Prostate Tumor Development in Transgenic Adenocarcinoma of Mouse Prostate: Role of Tumor Necrosis Factor-α–Stimulated Gene 6 , 2006, Clinical Cancer Research.

[63]  M. Collins,et al.  Ron receptor signaling augments mammary tumor formation and metastasis in a murine model of breast cancer. , 2005, Cancer research.

[64]  P. Hylemon,et al.  Diet, anaerobic bacterial metabolism, and colon cancer: a review of the literature. , 2005, Journal of clinical gastroenterology.

[65]  C. Van Waes,et al.  2-Methoxyestradiol Inhibits Hypoxia-Inducible Factor 1α, Tumor Growth, and Angiogenesis and Augments Paclitaxel Efficacy in Head and Neck Squamous Cell Carcinoma , 2004, Clinical Cancer Research.

[66]  A. Tarnawski,et al.  Deoxycholic acid activates beta-catenin signaling pathway and increases colon cell cancer growth and invasiveness. , 2004, Molecular biology of the cell.

[67]  John D. Storey,et al.  Statistical significance for genomewide studies , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[68]  J. Simons,et al.  2ME2 inhibits tumor growth and angiogenesis by disrupting microtubules and dysregulating HIF. , 2003, Cancer cell.

[69]  T. Slaga,et al.  2‐methoxyestradiol blocks cell‐cycle progression at G2/M phase and inhibits growth of human prostate cancer cells , 2001, Molecular carcinogenesis.

[70]  A. Ostman,et al.  Regulation of receptor tyrosine kinase signaling by protein tyrosine phosphatases. , 2001, Trends in cell biology.

[71]  D. Hanahan,et al.  The Hallmarks of Cancer , 2000, Cell.

[72]  J. Dekernion,et al.  Diagnosis and treatment of prostate cancer. , 1998, American family physician.

[73]  M. Kattan,et al.  Androgen-independent prostate cancer progression in the TRAMP model. , 1997, Cancer research.

[74]  J. Rosen,et al.  Metastatic prostate cancer in a transgenic mouse. , 1996, Cancer research.

[75]  T. Guthrie,et al.  Prostate cancer. , 2020, American family physician.

[76]  E. Wynder,et al.  Promoting effect of bile acids in colon carcinogenesis in germ-free and conventional F344 rats. , 1977, Cancer research.

[77]  I. N. Sneddon.  The relation between load and penetration in the axisymmetric boussinesq problem for a punch of arbitrary profile , 1965 .