Prostate cancer is responsible for over 30,000 US deaths annually, attributed largely to incurable metastatic disease. Here, we demonstrate that high levels of plectin are associated with localized and metastatic human prostate cancer when compared to benign prostate tissues. Knock-down of plectin inhibits prostate cancer cell growth and colony formation in vitro, and growth of prostate cancer xenografts in vivo. Plectin knock-down further impairs aggressive and invasive cellular behavior assessed by migration, invasion, and wound healing in vitro. Consistently, plectin knock-down cells have impaired metastatic colonization to distant sites including liver, lung, kidney, bone, and genitourinary system. Plectin knock-down inhibited number of metastases per organ, as well as decreased overall metastatic burden. To gain insights into the role of plectin in prostate cancer growth and metastasis, we performed proteomic analysis of prostate cancer plectin knock-down xenograft tissues. Gene set enrichment analysis shows an increase in levels of proteins involved with extracellular matrix and laminin interactions, and a decrease in levels of proteins regulating amino acid metabolism, cytoskeletal proteins, and cellular response to stress. Collectively these findings demonstrate that plectin is an important regulator of prostate cancer cell growth and metastasis.
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Siegel RL, Miller KD, Jemal A. Cancer statistics, 2020. CA: Cancer J Clin. 2020;70:7–30.
Bubendorf L, Schopfer A, Wagner U, Sauter G, Moch H, Willi N, et al. Metastatic patterns of prostate cancer: an autopsy study of 1,589 patients. Hum Pathol. 2000;31:578–83.
Drake CG. Visceral metastases and prostate cancer treatment: ‘die hard,’ ‘tough neighborhoods,’ or ‘evil humors’? Oncol (Williston Park). 2014;28:974–80.
Bekelman JE, Rumble RB, Chen RC, Pisansky TM, Finelli A, Feifer A. et al. Clinically Localized Prostate Cancer: ASCO Clinical Practice Guideline Endorsement of an American Urological Association/American Society for Radiation Oncology/Society of Urologic Oncology Guideline. J Clin Oncol. 2018;14:618–24.
Damber JE, Aus G. Prostate cancer. Lancet. 2008;371:1710–21.
de Bono JS, Logothetis CJ, Molina A, Fizazi K, North S, Chu L, et al. Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med. 2011;364:1995–2005.
Fizazi K, Scher HI, Molina A, Logothetis CJ, Chi KN, Jones RJ, et al. Abiraterone acetate for treatment of metastatic castration-resistant prostate cancer: final overall survival analysis of the COU-AA-301 randomised, double-blind, placebo-controlled phase 3 study. Lancet Oncol. 2012;13:983–92.
Ryan CJ, Smith MR, Fong L, Rosenberg JE, Kantoff P, Raynaud F, et al. Phase I clinical trial of the CYP17 inhibitor abiraterone acetate demonstrating clinical activity in patients with castration-resistant prostate cancer who received prior ketoconazole therapy. J Clin Oncol. 2010;28:1481–8.
Ryan CJ, Smith MR, de Bono JS, Molina A, Logothetis CJ, de Souza P, et al. Abiraterone in metastatic prostate cancer without previous chemotherapy. N Engl J Med. 2013;368:138–48.
Ryan CJ, Smith MR, Fizazi K, Saad F, Mulders PF, Sternberg CN, et al. Abiraterone acetate plus prednisone versus placebo plus prednisone in chemotherapy-naive men with metastatic castration-resistant prostate cancer (COU-AA-302): final overall survival analysis of a randomised, double-blind, placebo-controlled phase 3 study. Lancet Oncol. 2015;16:152–60.
Beer TM, Armstrong AJ, Rathkopf DE, Loriot Y, Sternberg CN, Higano CS, et al. Enzalutamide in metastatic prostate cancer before chemotherapy. N Engl J Med. 2014;371:424–33.
Evans CP, Higano CS, Keane T, Andriole G, Saad F, Iversen P, et al. The PREVAIL Study: primary Outcomes by Site and Extent of Baseline Disease for Enzalutamide-treated Men with Chemotherapy-naïve Metastatic Castration-resistant Prostate Cancer. Eur Urol. 2016;70:675–83.
Graff JN, Gordon MJ, Beer TM. Safety and effectiveness of enzalutamide in men with metastatic, castration-resistant prostate cancer. Expert Opin Pharmacother. 2015;16:749–54.
Rice MA, Malhotra SV, Stoyanova T. Second-Generation Antiandrogens: from Discovery to Standard of Care in Castration Resistant Prostate Cancer. Front Oncol. 2019;9:801.
Kyriakopoulos CE, Chen Y-H, Carducci MA, Liu G, Jarrard DF, Hahn NM, et al. Chemohormonal Therapy in Metastatic Hormone-Sensitive Prostate Cancer: Long-Term Survival Analysis of the Randomized Phase III E3805 CHAARTED Trial. J Clin Oncol. 2018;36:1080–7.
de Wit R, de Bono J, Sternberg CN, Fizazi K, Tombal B, Wülfing C, et al. Cabazitaxel versus Abiraterone or Enzalutamide in Metastatic Prostate Cancer. N Engl J Med. 2019;381:2506–18.
Small EJ, Schellhammer PF, Higano CS, Redfern CH, Nemunaitis JJ, Valone FH, et al. Placebo-Controlled Phase III Trial of Immunologic Therapy with Sipuleucel-T (APC8015) in Patients with Metastatic, Asymptomatic Hormone Refractory Prostate Cancer. J Clin Oncol. 2006;24:3089–94.
Wiche G. Role of plectin in cytoskeleton organization and dynamics. J Cell Sci. 1998;111(Pt 17):2477–86.
Ševčík J, Urbániková L, Košt’an J, Janda L, Wiche G. Actin-binding domain of mouse plectin. Eur J Biochem. 2004;271:1873–84.
Sutoh Yoneyama M, Hatakeyama S, Habuchi T, Inoue T, Nakamura T, Funyu T, et al. Vimentin intermediate filament and plectin provide a scaffold for invadopodia, facilitating cancer cell invasion and extravasation for metastasis. Eur J Cell Biol. 2014;93:157–69.
Burgstaller G, Gregor M, Winter L, Wiche G. Keeping the vimentin network under control: cell-matrix adhesion-associated plectin 1f affects cell shape and polarity of fibroblasts. Mol Biol Cell. 2010;21:3362–75.
Osmanagic-Myers S, Rus S, Wolfram M, Brunner D, Goldmann WH, Bonakdar N, et al. Plectin reinforces vascular integrity by mediating crosstalk between the vimentin and the actin networks. J Cell Sci. 2015;128:4138.
Raymond AC, Gao B, Girard L, Minna JD, Gomika Udugamasooriya D. Unbiased peptoid combinatorial cell screen identifies plectin protein as a potential biomarker for lung cancer stem cells. Sci Rep. 2019;9:14954.
Wiche G, Winter L. Plectin isoforms as organizers of intermediate filament cytoarchitecture. Bioarchitecture. 2011;1:14–20.
Winter L, Wiche G. The many faces of plectin and plectinopathies: pathology and mechanisms. Acta Neuropathol. 2013;125:77–93.
Osmanagic-Myers S, Wiche G. Plectin-RACK1 (receptor for activated C kinase 1) scaffolding: a novel mechanism to regulate protein kinase C activity. J Biol Chem. 2004;279:18701–10.
Osmanagic-Myers S, Gregor M, Walko G, Burgstaller G, Reipert S, Wiche G. Plectin-controlled keratin cytoarchitecture affects MAP kinases involved in cellular stress response and migration. J Cell Biol. 2006;174:557–68.
Bausch D, Thomas S, Mino-Kenudson M, Fernández-del CC, Bauer TW, Williams M, et al. Plectin-1 as a Novel Biomarker for Pancreatic Cancer. Clin Cancer Res. 2011;17:302–9.
Katada K, Tomonaga T, Satoh M, Matsushita K, Tonoike Y, Kodera Y, et al. Plectin promotes migration and invasion of cancer cells and is a novel prognostic marker for head and neck squamous cell carcinoma. J Proteom. 2012;75:1803–15.
Shin SJ, Smith JA, Rezniczek GA, Pan S, Chen R, Brentnall TA, et al. Unexpected gain of function for the scaffolding protein plectin due to mislocalization in pancreatic cancer. Proc Natl Acad Sci. 2013;110:19414–9.
Koster J, van Wilpe S, Kuikman I, Litjens SHM, Sonnenberg A. Role of binding of plectin to the integrin beta4 subunit in the assembly of hemidesmosomes. Mol Biol Cell. 2004;15:1211–23.
Litjens SH, de Pereda JM, Sonnenberg A. Current insights into the formation and breakdown of hemidesmosomes. Trends Cell Biol. 2006;16:376–83.
Song J-G, Kostan J, Drepper F, Knapp B, de Almeida Ribeiro E Jr., Konarev Petr V, et al. Structural Insights into Ca2+-Calmodulin Regulation of Plectin 1a-Integrin β4 Interaction in Hemidesmosomes. Structure. 2015;23:558–70.
Andra K, Lassmann H, Bittner R, Shorny S, Fassler R, Propst F, et al. Targeted inactivation of plectin reveals essential function in maintaining the integrity of skin, muscle, and heart cytoarchitecture. Genes Dev. 1997;11:3143–56.
Humphreys DT, Carver JA, Easterbrook-Smith SB, Wilson MR. Clusterin Has Chaperone-like Activity Similar to That of Small Heat Shock Proteins. J Biol Chem. 1999;274:6875–81.
Peng M, Deng J, Zhou S, Tao T, Su Q, Yang X, et al. The role of Clusterin in cancer metastasis. Cancer Manag Res. 2019;11:2405–14.
Shapiro B, Tocci P, Haase G, Gavert N, Ben-Ze’ev A. Clusterin, a gene enriched in intestinal stem cells, is required for L1-mediated colon cancer metastasis. Oncotarget. 2015;6:34389–401.
Wang C, Jin G, Jin H, Wang N, Luo Q, Zhang Y, et al. Clusterin facilitates metastasis by EIF3I/Akt/MMP13 signaling in hepatocellular carcinoma. Oncotarget. 2015;6:2903–16.
Zhu Y, Chen P, Gao Y, Ta N, Zhang Y, Cai J, et al. MEG3 Activated by Vitamin D Inhibits Colorectal Cancer Cells Proliferation and Migration via Regulating Clusterin. EBioMedicine. 2018;30:148–57.
Kim N, Han JY, Roh GS, Kim HJ, Kang SS, Cho GJ, et al. Nuclear clusterin is associated with neuronal apoptosis in the developing rat brain upon ethanol exposure. Alcohol Clin Exp Res. 2012;36:72–82.
Scaltriti M, Santamaria A, Paciucci R, Bettuzzi S. Intracellular Clusterin Induces G2/M Phase Arrest and Cell Death in PC-3 Prostate Cancer Cells. Cancer Res. 2004;64:6174–82.
Knott SRV, Wagenblast E, Khan S, Kim SY, Soto M, Wagner M, et al. Asparagine bioavailability governs metastasis in a model of breast cancer. Nature. 2018;554:378–81.
Porporato PE, Payen VL, Baselet B, Sonveaux P. Metabolic changes associated with tumor metastasis, part 2: Mitochondria, lipid and amino acid metabolism. Cell Mol Life Sci. 2016;73:1349–63.
Zhou W, Gui M, Zhu M, Long Z, Huang L, Zhou J, et al. Nicotinamide N-methyltransferase is overexpressed in prostate cancer and correlates with prolonged progression-free and overall survival times. Oncol Lett. 2014;8:1175–80.
DeBerardinis RJ, Cheng T. Q’s next: the diverse functions of glutamine in metabolism, cell biology and cancer. Oncogene. 2010;29:313–24.
Strmiska V, Michalek P, Eckschlager T, Stiborova M, Adam V, Krizkova S, et al. Prostate cancer-specific hallmarks of amino acids metabolism: towards a paradigm of precision medicine. Biochim Biophys Acta Rev Cancer. 2019;1871:248–58.
Burch TC, Watson MT, Nyalwidhe JO. Variable metastatic potentials correlate with differential plectin and vimentin expression in syngeneic androgen independent prostate cancer cells. PLoS ONE. 2013;8:e65005–e65005.
Huang J, Yao JL, Zhang L, Bourne PA, Quinn AM, di Sant’Agnese PA, et al. Differential expression of interleukin-8 and its receptors in the neuroendocrine and non-neuroendocrine compartments of prostate cancer. Am J Pathol. 2005;166:1807–15.
Wang J, Place RF, Huang V, Wang X, Noonan EJ, Magyar CE, et al. Prognostic value and function of KLF4 in prostate cancer: RNAa and vector-mediated overexpression identify KLF4 as an inhibitor of tumor cell growth and migration. Cancer Res. 2010;70:10182–91.
Hsu EC, Rice MA, Bermudez A, Marques FJG, Aslan M, Liu S, et al. Trop2 is a driver of metastatic prostate cancer with neuroendocrine phenotype via PARP1. Proc Natl Acad Sci USA. 2020;117:2032–42.
Rice MA, Hsu EC, Aslan M, Ghoochani A, Su A, Stoyanova T. Loss of Notch1 activity inhibits prostate cancer growth and metastasis and sensitizes prostate cancer cells to anti-androgen therapies. Mol Cancer Ther. 2019;18:1230–42.
Stoyanova T, Riedinger M, Lin S, Faltermeier CM, Smith BA, Zhang KX, et al. Activation of Notch1 synergizes with multiple pathways in promoting castration-resistant prostate cancer. Proc Natl Acad Sci USA. 2016;113:E6457–66.
Sarbassov DD, Guertin DA, Ali SM, Sabatini DM. Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science. 2005;307:1098–101.
Schindelin J, Arganda-Carreras I, Frise E, Kaynig V, Longair M, Pietzsch T, et al. Fiji: an open-source platform for biological-image analysis. Nat Methods. 2012;9:676–82.
Gatto L, Lilley KS. MSnbase-an R/Bioconductor package for isobaric tagged mass spectrometry data visualization, processing and quantitation. Bioinformatics. 2012;28:288–9.
Navarro P, Trevisan-Herraz M, Bonzon-Kulichenko E, Nunez E, Martinez-Acedo P, Perez-Hernandez D, et al. General statistical framework for quantitative proteomics by stable isotope labeling. J Proteome Res. 2014;13:1234–47.
Tyanova S, Temu T, Sinitcyn P, Carlson A, Hein MY, Geiger T, et al. The Perseus computational platform for comprehensive analysis of (prote)omics data. Nat Methods. 2016;13:731–40.
Mi H, Muruganujan A, Huang X, Ebert D, Mills C, Guo X, et al. Protocol Update for large-scale genome and gene function analysis with the PANTHER classification system (v.14.0). Nat Protoc. 2019;14:703–21.
Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA, et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci. 2005;102:15545.
TS is supported by Canary Foundation, National Institutes of Health/National Cancer Institute (NCI) R37CA240822, R01CA244281 and R03CA230819. TS was also supported by the U.S. Army Medical Research Acquisition Activity through the Congressionally Directed Medical Research Program (CDMRP) Award No. W81XWH1810323. MAR is supported by the U.S. Army Medical Research Acquisition Activity, through the CDMRP Award No. W81XWH1810141. Research reported in this publication was supported in part by the National Institutes of Health under award number S10 OD023518–01A1 for the Celigo S Imaging Cytometer (200-BFFL-S). Opinions, interpretation, conclusions and recommendations are those of the authors and not necessarily endorsed by the US Army and the funding agencies.
TS is supported by the Canary Foundation, the National Institutes of Health/National Cancer Institute (NCI) R37CA240822, R01CA244281 and R03CA230819. MAR is supported by the CDMRP through Award No. W81XWH1810141.
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Buckup, M., Rice, M.A., Hsu, EC. et al. Plectin is a regulator of prostate cancer growth and metastasis. Oncogene (2020). https://doi.org/10.1038/s41388-020-01557-9