A. Abbruzzese

D. Gentilini

G. Vitale

M. Caraglia

English

Giovanni Vitale

Davide Gentilini

Alberto Abbruzzese

Michele Caraglia

Crossref

Cancer Biology & Therapy

Pyk2 and Cyr61 at the cross-road of cAMP-dependent signalling in invasiveness and neuroendocrine differentiation of prostate cancer

Vitale, Giovanni

Gentilini, Davide

Abbruzzese, Alberto

Caraglia, Michele

Archivio Istituzionale della Ricerca - Università degli Studi di Pavia

AIR Universita degli studi di Milano

Full Terms & Conditions of access and use can be found athttps://www.tandfonline.com/action/journalInformation?journalCode=kcbt20Cancer Biology & TherapyISSN: 1538-4047 (Print) 1555-8576 (Online) Journal homepage: https://www.tandfonline.com/loi/kcbt20Pyk2 and Cyr61 at the cross-road of cAMP-dependent signalling in invasiveness andneuroendocrine differentiation of prostate cancerGiovanni Vitale, Davide Gentilini, Alberto Abbruzzese & Michele CaragliaTo cite this article: Giovanni Vitale, Davide Gentilini, Alberto Abbruzzese & Michele Caraglia(2009) Pyk2 and Cyr61 at the cross-road of cAMP-dependent signalling in invasiveness andneuroendocrine differentiation of prostate cancer, Cancer Biology & Therapy, 8:3, 243-244, DOI:10.4161/cbt.8.3.7616To link to this article:  https://doi.org/10.4161/cbt.8.3.7616Published online: 01 Feb 2009.Submit your article to this journal Article views: 102View related articles [Cancer Biology & Therapy 8:3, 243-244; 1 February 2009]; ©2009 Landes BioscienceIn this issue of Cancer Biology & Therapy, Kisslinger et al. demon-strated for the first time that Proline-rich tyrosine kinase (Pyk2) and cAMP interact in regulating prostate cell functions and in “keeping” prostate identity.1 In EPN cells, a line of non-transfomed epithelial cells derived from human normal tissue, cAMP potently inhibits growth (~90% after eight days) and preserves prostate differentiation through Pyk2 phosphorylation. The antiproliferative effect medi-ated by Pyk2 activation seems to be a consequence of abolishing AKT1 phosphorylation. While in EPN-PKM3 cells, an EPN clone bearing a Pyk2 kinase-negative mutant, cAMP incubation induces a moderate inhibition in cell proliferation (-35%), the remaining AKT1 was still activated for up to 72 hours and shifted prostate cells towards a neuroendocrine phenotype. In fact, analysis of the expres-sion of the HOX gene network revealed that Pyk2 function alone did not affect HOX gene expression, but cAMP stimulation induced a modulation of HOX D and C genes, which are involved in neuroen-docrine differentiation.Pyk2 is a non-receptor tyrosine kinase of the focal adhesion kinase (FAK) family, involved in several cellular functions such as adhesion, motility, anchorage independence, cell proliferation, apoptosis and the G1 to S phase transition of the cell cycle.2,3 Pyk2 seems to have a main role in the tumorigenesis, differentiation and invasiveness of prostate cancer. In fact, Pyk2 is functionally expressed in both normal and neoplastic prostate tissue. The expression of this tyrosine kinase is inversely correlated to the degree of prostate malignancy. Pyk2 progressively decreases as the grade of the adenocarcinoma increases until disappearing in anaplastic, undifferentiated cancer.4,5 This suggests that in the prostate Pyk2 may play the role of an onco-suppressor gene, while its expression or lack of expression could reflect the state of differentiation of the tumor. In addition, a decrease in the expression of Pyk2 resulted in a MAP kinase-dependent decrease in the proliferation of prostate cells, while the loss of Pyk2 kinase activity in EPN-PKM3 cells correlated with increased cell motility and migration.6,7 However, most of these data were obtained in non-transformed epithelial cells, while several studies on prostate cancer cells suggest an involvement of Pyk2 activation in invasion processes.8,9 Therefore, an inverse role of Pyk2 in cancer cells cannot be excluded; where signal transduction pathways are deregulated and the normal interactions and feed-back loops between proliferative and growth suppressing pathways are lacking due to multiple muta-tions acting at several levels.In most cases Pyk2 is involved in integrin-mediated signal trans-duction. Pyk2 is activated after integrin clustering in response to various extracellular matrix components, such as fibronectin and by a number of growth factor receptors, including ErbB tyrosine kinases. After activation, Pyk2 undergoes multiple phosphorylations and engages in protein-protein interactions with a variety of proteins including cytoskeletal proteins, such as paxillin; tyrosine kinases, such as Src and C-terminal src-kinase; serine/threonine kinases, such as integrin-linked kinase and p21-activated kinase; and modulators of small GTPases of the Rho family. These multiple interactions have been established as critical regulators of early cell invasion signalling, promoting cancer cell migration and the initiation of metastasis formation.3 In EPN-PKM3 prostate cells the loss of Pyk2 activity upregulates expression of the α5-integrin subunit, which mediates adhesion to fibronectin.7 Expression of α5-integrin correlates with the resistance of prostate cancer cells to undergo apoptosis.10,11 In the human prostate cancer cell line PC-3, upregulation of α5-integrin is associated with increased adhesion to the extracellular matrix protein fibronectin, thereby facilitating colonization of the bone matrix where these cells preferentially metastasize.12,13 Therefore Pyk2 plays a central role in the mechanisms that regulate cell-cell and cell-substrate interactions. The lack of Pyk2 kinase activity induces normal prostate cells to acquire a malignant, invasive, highly prolif-erating and migrating phenotype.Cyr61, a member of growth factor-inducible immediate-early genes belonging to the CCN family, plays an important role in cell proliferation, adhesion and differentiation of prostatic stromal and epithelial cells and in the processes of tumorigenesis and inva-siveness of prostate cancer.14-16 These biological properties are mainly modulated by interactions with cell surface integrins because Cyr61 functions as a bridge between cell membrane integrins and *Correspondence to: Giovanni Vitale; Istituto Auxologico Italiano; Via Zucchi 18; Cusano Milanino (MI); Milan 20095 Italy; Email: vanni10@yahoo.comSubmitted: 11/08/08; Accepted: 12/11/08Previously published online as a Cancer Biology & Therapy E-publication: http://www.landesbioscience.com/journals/cbt/article/7616Commentary to: Kisslinger A, Cantile M, Sparaneo G, Vitale N, Fabbrocini G, Chieffi P, Cillo C, Mancini FP, Tramontano D. cAMP and Pyk2 interact to regulate prostate cell proliferation and function. Cancer Biol Ther 2009; This issue.CommentaryPyk2 and Cyr61 at the cross-road of cAMP-dependent signalling in  invasiveness and neuroendocrine differentiation of prostate cancerGiovanni Vitale,1,2,* Davide Gentilini,2 Alberto Abbruzzese3 and Michele Caraglia31Department of Medical Sciences; University of Milan; Milan, Italy; 2Istituto Auxologico Italiano IRCCS; Milan, Italy; 3Department of Biochemistry and Biophysics; Second University of Naples; Naples, ItalyKey words: Pyk2, Cyr61, prostate cancer, integrins, differentiation, invasiveness, proliferationwww.landesbioscience.com Cancer Biology & Therapy 243Role of Pyk2 and Cyr61 in prostate cancerextracellular matrix components (i.e., fibronectin). In PCa, a pros-tate cancer cell line, Cyr61 regulated the level of activated Rac1 as well as its downstream targets, including phosphorylated JNK, E-cadherin and p27(kip1), which are key molecules involved in cell growth, migration and invasion.16 In other tumor models it has been shown that CYR61 cooperates with integrins to promote metastasis, peritoneal disseminations, tumour proliferation and resistance to apoptosis.17-20It is interesting to observe that as for Pyk2, Cyr61 is regulated through the cAMP signal transduction pathway. In fact, cAMP responsive element-binding protein (CREB) positively regulates the expression of Cyr61 in response to hypoxia in vitro and activates Cyr61 gene expression in correlation with hypoxic regions in tumors in vivo.21 Therefore, cAMP increases the expression of both Cyr61 and Pyk2. It will be important to check the interaction between Pyk2 and Cyr61 in these experimental models and their correlations with the cAMP-dependent pathway, cell proliferation, neuroendocrine differentiation and tumor invasiveness (Fig. 1). The interaction between components of the machinery involved in the control of cell adhesion and motility could have a pivotal role in the regulation of both proliferation and cAMP-mediated commitment to neuro-endocrine differentiation. In this view, a series of potential proteins for stromal signaling and the bladder or prostate differentiation program including cathepsin L, follistatin-related protein, neuroen-docrine convertase, tumor necrosis factor receptor and others was recently identified. The prostate stromal/epithelial signaling may be accomplished through activation of the interaction between extracel-lular matrix molecules and receptors, complement and coagulation cascades, focal adhesion and cell adhesion pathways (including Pyk2).22 In conclusion, the data by Kisslinker et al.1 may provide a new class of targets that can be used for the design of new strategies in prostate cancer treatment.References 1. Kisslinger A, Cantile M, Sparaneo G, Vitale N, Fabbrocini G, Chieffi P, et al. cAMP and Pyk2 interact to regulate prostate cell proliferation and function. Cancer Biol Ther 2009; 8:236-42. 2. Gelman IH. Pyk 2 FAKs, any two FAKs. Cell Biol Int 2003; 27:507-10. 3. Behmoaram E, Bijian K, Jie S, Xu Y, Darnel A, Bismar TA, et al. Focal adhesion kinase-related proline-rich tyrosine kinase 2 and focal adhesion kinase are co-overexpressed in early-stage and invasive ErbB-2-positive breast cancer and cooperate for breast cancer cell tumorigenesis and invasiveness. Am J Pathol 2008; 173:1540-50. 4. Stanzione R, Picascia A, Chieffi P, Imbimbo C, Palmieri A, Mirone V, et al. Variations of proline-rich kinase Pyk2 expression correlate with prostate cancer progression. Lab Invest 2001; 81:51-9. 5. Picascia A, Stanzione R, Chieffi P, Kisslinger A, Dikic I, Tramontano D. Proline-rich tyrosine kinase 2 regulates proliferation and differentiation of prostate cells. Mol Cell Endocrinol 2002; 186:81-7. 6. Wang X, Yang Y, Guo X, Sampson ER, Hsu CL, Tsai MY, et al. Suppression of androgen receptor transactivation by Pyk2 via interaction and phosphorylation of the ARA55 coregu-lator. J Biol Chem 2002; 277:15426-31. 7. de Amicis F, Lanzino M, Kisslinger A, Cali G, Chieffi P ando S, Mancini FP, et al. Loss of proline-rich tyrosine kinase 2 function induces spreading and motility of epithelial prostate cells. J Cell Physiol 2006; 209:74-80. 8. Iiizumi M, Bandyopadhyay S, Pai SK, Watabe M, Hirota S, Hosobe S, et al. RhoC promotes metastasis via activation of the Pyk2 pathway in prostate cancer. Cancer Res 2008; 68:7613-20. 9. Sahu SN, Nunez S, Bai G, Gupta A. Interaction of Pyk2 and PTP-PEST with leupaxin in prostate cancer cells. Am J Physiol Cell Physiol 2007; 292:2288-96. 10. Chatterjee S, Brite KH, Matsumura A. Induction of apoptosis of integrin expressing human prostate cancer cells by cyclic arg-gly-asp peptides. Clin Cancer Res 2001; 7:3006-11. 11. Nagakawa O, Akashi T, Hayakawa Y, Junicho A, Koizumi K, Fujiuchi Y, et al. Differential expression of integrin subunits in DU-145/AR prostate cancer cells. Oncol Rep 2004; 4:837-41. 12. Shen X, Falzon M. PTH-related proteinmodulates PC-3 prostate cancer cell adhesion and integrin subunit profile. Mol Cell Endocrinol 2003; 199:165-77. 13. Tantivejkul K, Kalikin LM, Pienta KJ. Dynamic process of prostate cancer metastasis to bone. J Cell Biochem 2004; 91:706-17. 14. Chen Y, Du XY. Functional properties and intracellular signaling of CCN1/Cyr61. J Cell Biochem 2007; 100:1337-45. 15. Sakamoto S, Yokoyama M, Aoki M, Suzuki K, Kakehi Y, Saito Y. Induction and function of CYR61 (CCN1) in prostatic stromal and epithelial cells: CYR61 is required for prostatic cell proliferation. Prostate 2004; 61:305-17. 16. Sun ZJ, Wang Y, Cai Z, Chen PP, Tong XJ, Xie D. Involvement of Cyr61 in growth, migra-tion and metastasis of prostate cancer cells. Br J Cancer 2008; 99:1656-67. 17. Monnier Y, Farmer P, Bieler G, Imaizumi N, Sengstag T, Alghisi GC, et al. CYR61 and AVB5 integrin cooperate to promote invasion and metastasis of tumors growing in preir-radiated stroma. Cancer Res 2008; 68:7323-31. 18. Lin MT, Chang CC, Lin BR, Yang HY, Chu CY, Wu MH, et al. Elevated expression of Cyr61 enhances peritoneal dissemination of gastric cancer cells through integrin alpha2-beta1. J Biol Chem 2007; 282:34594-604. 19. Vellon L, Menendez JA, Lupu R. AlphaVbeta3 integrin regulates heregulin (HRG)-induced cell proliferation and survival in breast cancer. Oncogene 2005; 24:3759-73. 20. Lin MT, Chang CC, Chen ST, Chang HL, Su JL, Chau YP, et al. Cyr61 expression confers resistance to apoptosis in breast cancer MCF-7 cells by a mechanism of NF-kappaB-dependent XIAP upregulation. J Biol Chem 2004; 279:24015-23. 21. Meyuhas R, Pikarsky E, Tavor E, Klar A, Abramovitch R, Hochman J, et al. A key role for cyclic AMP-responsive element binding protein in hypoxia-mediated activation of the angiogenesis factor CCN1(CYR61) in tumor cells. Mol Cancer Res 2008; 6:1397-409. 22. Goo YA, Liu AY, Ryu S, Shaffer SA, Malmström L, Page L, et al. Identification of secreted glycoproteins of human prostate and bladder stromal cells by comparative quantitative proteomics. Prostate 2009; 69:49-61.Figure 1. Hypothesis of the interaction between Pyk2 and Cyr61 under the control of the cAMP-dependent pathway in the modulation of cell proliferation, neuroendocrine differentiation and tumor invasiveness in prostate cancer.244 Cancer Biology & Therapy 2009; Vol. 8 Issue 3

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Pyk2 and Cyr61 at the cross-road of cAMP-dependent signalling in invasiveness and neuroendocrine differentiation of prostate cancer

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