Abstract
The identification of new factors that may function as cancer markers and become eventual pharmacologic targets is a challenge that may influence the management of tumor development and management. Recent discoveries connecting Hsp90-binding immunophilins with the regulation of signalling events that can modulate cancer progression transform this family of proteins in potential unconventional factors that may impact on the screening and diagnosis of malignant diseases. Immunophilins are molecular chaperones that group a family of intracellular receptors for immunosuppressive compounds. A subfamily of the immunophilin family is characterized by showing structural tetratricopeptide repeats, protein domains that are able to interact with the C-terminal end of the molecular chaperone Hsp90, and via the proper Hsp90-immunophilin complex, the biological properties of a number of client-proteins involved in cancer biology are modulated. Recent discoveries have demonstrated that two of the most studied members of this Hsp90- binding subfamily of immunophilins, FKBP51 and FKBP52, participate in several cellular processes such as apoptosis, carcinogenesis progression, and chemoresistance. While the expression levels of some members of the immunophilin family are affected in both cancer cell lines and human cancer tissues compared to normal samples, novel regulatory mechanisms have emerged during the last few years for several client-factors of immunophilins that are major players in cancer development and progression, among them steroid receptors, the transctiption factor NF-κB and the catalytic subunit of telomerase, hTERT. In this review, recent findings related to the biological properties of both iconic Hsp90-binding immunophilins, FKBP51 and FKBP52, are reviewed within the context of their interactions with those chaperoned client-factors. The potential roles of both immunophilins as potential cancer biomarkers and non-conventional pharmacologic targets for cancer treatment are discussed.
Keywords: Heat-shock proteins, immunophilins, cancer, peptidylprolyl isomerase, TPR protein, steroid receptor, NF-κB.
Graphical Abstract
[1]
Erlejman AG, Lagadari M, Galigniana MD. Hsp90-binding immunophilins as a potential new platform for drug treatment. Future Med Chem 2013; 5(5): 591-607.
[2]
Galigniana MD. Editorial: Immunophilins, protein chemistry and cell biology of a promising new class of drug targets - Part II. Curr Mol Pharmacol 2016; 9(2): 97-8.
[4]
Dumont FJ. FK506, an immunosuppressant targeting calcineurin function. Curr Med Chem 2000; 7(7): 731-48.
[5]
Storer CL, Dickey CA, Galigniana MD, Rein T, Cox MB. FKBP51 and FKBP52 in signaling and disease. Trends Endocrinol Metabol 2011; 22(12): 481-90.
[6]
Cox MB, Smith DF. Functions of the Hsp90-bindign FKBP immunophilins. Subcell Biochem 2015; 78: 35-68.
[7]
Ratajczak T, Cluning C, Ward BK. Steroid receptor-associated immunophilins: A gateway to steroid signalling. Clin Biochem Rev 2015; 36(2): 31-52.
[8]
Young JC, Obermann WM, Hartl FU. Specific binding of tetratricopeptide repeat proteins to the C-terminal 12-kDa domain of hsp90. J Biol Chem 1998; 273(29): 18007-10.
[9]
Blundell KL, Pal M, Roe SM, Pearl LH, Prodromou C. The structure of FKBP38 in complex with the MEEVD tetratricopeptide binding-motif of Hsp90. PloS One 2017; 12(3)e0173543
[10]
Jascur T, Brickner H, Salles-Passador I, et al. Regulation of p21(WAF1/CIP1) stability by WISp39, a Hsp90 binding TPR protein. Mol Cell 2005; 17(2): 237-49.
[11]
Silverstein AM, Galigniana MD, Chen MS, Owens-Grillo JK, Chinkers M, Pratt WB. Protein phosphatase 5 is a major component of glucocorticoid receptor.hsp90 complexes with properties of an FK506-binding immunophilin. J Biol Chem 1997; 272(26): 16224-30.
[12]
Meyer BK, Petrulis JR, Perdew GH. Aryl hydrocarbon (Ah) receptor levels are selectively modulated by hsp90-associated immunophilin homolog XAP2. Cell Stress chaperone 2000; 5(3): 243-54.
[14]
Calderwood SK. Heat shock proteins and cancer: Intracellular chaperones or extracellular signalling ligands? Philosophical transactions of the Royal Society of London Series. B Biol Sci 2018; 373: 1738.
[15]
Jhaveri K, Taldone T, Modi S, Chiosis G. Advances in the clinical development of heat shock protein 90 (Hsp90) inhibitors in cancers. Biochim Biophys Acta 2012; 1823(3): 742-55.
[16]
Shrestha L, Bolaender A, Patel HJ, Taldone T. Heat Shock Protein (HSP) drug discovery and development: Targeting heat shock proteins in disease. Curr Topics Med Chem 2016; 16(25): 2753-64.
[17]
Jhaveri K, Ochiana SO, Dunphy MP, et al. Heat shock protein 90 inhibitors in the treatment of cancer: Current status and future directions. Expert Opin Investigat Drugs 2014; 23(5): 611-28.
[18]
Chatterjee S, Burns TF. Targeting heat shock proteins in cancer: A promising therapeutic approach. Int J Mol Sci 2017; 18(9)E1978
[19]
Trepel J, Mollapour M, Giaccone G, Neckers L. Targeting the dynamic HSP90 complex in cancer. Nat Rev Cancer 2010; 10(8): 537-49.
[20]
Hendriks LEL, Dingemans AC. Heat shock protein antagonists in early stage clinical trials for NSCLC. Expert Opin Investig Drugs 2017; 26(5): 541-50.
[21]
Yuno A, Lee MJ, Lee S, et al. Clinical evaluation and biomarker profiling of Hsp90 inhibitors. Methods Mol Biol 2018; 1709: 423-41.
[22]
Prince T, Ackerman A, Cavanaugh A, et al. Dual targeting of HSP70 does not induce the heat shock response and synergistically reduces cell viability in muscle invasive bladder cancer. Oncotarget 2018; 9(66): 32702-17.
[23]
Piper PW, Millson SH. Mechanisms of resistance to HSP90 inhibitor drugs: A complex mosaic emerges. Pharmaceuticals 2011; 4(11): 1400-22.
[24]
Graner AN, Hellwinkel JE, Lencioni AM, et al. HSP90 inhibitors in the context of heat shock and the unfolded protein response: Effects on a primary canine pulmonary adenocarcinoma cell line. Int J Hyperthermia 2017; 33(3): 303-17.
[25]
Shah SP, Lonial S, Boise LH. When cancer fights back: Multiple myeloma, proteasome inhibition, and the heat-shock response. Mol Cancer Res 2015; 13(8): 1163-73.
[27]
Saif MW, Erlichman C, Dragovich T, et al. Open-label, dose-escalation, safety, pharmacokinetic, and pharmacodynamic study of intravenously administered CNF1010 (17-(allylamino)-17-demethoxygeldanamycin [17-AAG]) in patients with solid tumors. Cancer Chemother Pharmacol 2013; 71(5): 1345-55.
[28]
McCollum AK, Teneyck CJ, Sauer BM, Toft DO, Erlichman C. Up-regulation of heat shock protein 27 induces resistance to 17-allylamino-demethoxygeldanamycin through a glutathione-mediated mechanism. Cancer Res 2006; 66(22): 10967-75.
[29]
Nowakowski GS, McCollum AK, Ames MM, et al. A phase I trial of twice-weekly 17-allylamino-demethoxy-geldanamycin in patients with advanced cancer. Clinical Cancer Res 2006; 12(20): 6087-93.
[30]
Neckers L, Workman P. Hsp90 molecular chaperone inhibitors: Are we there yet? Clin Cancer Res 2012; 18(1): 64-76.
[31]
He Y, Peng S, Wang J, et al. Ailanthone targets p23 to overcome MDV3100 resistance in castration-resistant prostate cancer. Nat Commun 2016; 7: 13122.
[32]
Khan MS, Majid AM, Iqbal MA, Majid AS, Al-Mansoub M, Haque RS. Designing the angiogenic inhibitor for brain tumor via disruption of VEGF and IL17A expression. Eur J Pharmaceut Sci 2016; 93: 304-18.
[33]
Holmes JL, Sharp SY, Hobbs S, Workman P. Silencing of HSP90 cochaperone AHA1 expression decreases client protein activation and increases cellular sensitivity to the HSP90 inhibitor 17-allylamino-17-demethoxygeldanamycin. Cancer Res 2008; 68(4): 1188-97.
[34]
Smith JR, Workman P. Targeting CDC37: An alternative, kinase-directed strategy for disruption of oncogenic chaperoning. Cell Cycle 2009; 8(3): 362-72.
[35]
McDowell CL, Bryan Sutton R, Obermann WM. Expression of Hsp90 chaperone [corrected] proteins in human tumor tissue. Int J Biol Macromol 2009; 45(3): 310-4.
[36]
Schmid S, Gotz M, Hugel T. Effects of inhibitors on Hsp90's conformational dynamics, cochaperone and client interactions. Chemphyschem 2018; 19(14): 1716-21.
[37]
Mazaira GI, Camisay MF, De Leo S, Erlejman AG, Galigniana MD. Biological relevance of Hsp90-binding immunophilins in cancer development and treatment. Int J Cancer 2016; 138(4): 797-808.
[38]
McKeen HD, Brennan DJ, Hegarty S, et al. The emerging role of FK506-binding proteins as cancer biomarkers: A focus on FKBPL. Biochem Soc Transac 2011; 39(2): 663-8.
[39]
Koay YC, McConnell JR, Wang Y, et al. Chemically accessible hsp90 inhibitor that does not induce a heat shock response. ACS Med Chem Lett 2014; 5(7): 771-6.
[40]
McConnell JR, Alexander LA, McAlpine SR. A heat shock protein 90 inhibitor that modulates the immunophilins and regulates hormone receptors without inducing the heat shock response. Bioorg Med Chem Lett 2014; 24(2): 661-6.
[41]
Thoms S, Ali AI, Jonczyk R, Scheper T, Blume C. Tacrolimus inhibits angiogenesis and induces disaggregation of endothelial cells in spheroids - Toxicity testing in a 3D cell culture approach. Toxicol in vitro 2018; 53: 10-9.
[42]
Jiang W, Cazacu S, Xiang C, et al. FK506 binding protein mediates glioma cell growth and sensitivity to rapamycin treatment by regulating NF-kappaB signaling pathway. Neoplasia 2008; 10(3): 235-43.
[43]
Erlejman AG, De Leo SA, Mazaira GI, et al. NF-kappaB transcriptional activity is modulated by FK506-binding proteins FKBP51 and FKBP52: A role for peptidyl-prolyl isomerase activity. J Biol Chem 2014; 289(38): 26263-76.
[44]
Valentine A, O’Rourke M, Yakkundi A, et al. FKBPL and peptide derivatives: novel biological agents that inhibit angiogenesis by a CD44-dependent mechanism. Clin Cancer Res 2011; 17(5): 1044-56.
[45]
Joshi JB, Patel D, Morton DJ, et al. Inactivation of ID4 promotes a CRPC phenotype with constitutive AR activation through FKBP52. Mol Oncol 2017; 11(4): 337-57.
[46]
Ratajczak T. Steroid receptor-associated immunophilins: Candidates for diverse drug-targeting approaches in disease. Curr Mol Pharmacol 2015; 9(1): 66-95.
[47]
Fries GR, Gassen NC, Rein T. The FKBP51 Glucocorticoid receptor co-chaperone: Regulation, function, and implications in health and disease. Int J Mol Sci 2017; 18(12)E2614
[48]
Guy NC, Garcia YA, Sivils JC, Galigniana MD, Cox MB. Functions of the Hsp90-binding FKBP immunophilins. Subcell Biochem 2015; 78: 35-68.
[49]
Quintá HR, Maschi D, Gomez-Sanchez C, Piwien-Pilipuk G, Galigniana MD. Subcellular rearrangement of hsp90-binding immunophilins accompanies neuronal differentiation and neurite outgrowth. J Neurochem 2010; 115(3): 716-34.
[50]
Toneatto J, Guber S, Charo NL, et al. Dynamic mitochondrial-nuclear redistribution of the immunophilin FKBP51 is regulated by the PKA signaling pathway to control gene expression during adipocyte differentiation. J Cell Sci 2013; 126(Pt 23): 5357-68.
[51]
Gallo LI, Lagadari M, Piwien-Pilipuk G, Galigniana MD. The 90-kDa heat-shock protein (Hsp90)-binding immunophilin FKBP51 is a mitochondrial protein that translocates to the nucleus to protect cells against oxidative stress. J Biol Chem 2011; 286(34): 30152-60.
[52]
Bonner JM, Boulianne GL. Diverse structures, functions and uses of FK506 binding proteins. Cell Signal 2017; 38: 97-105.
[53]
Lagadari M, Zgajnar NR, Gallo LI, Galigniana MD. Hsp90-binding immunophilin FKBP51 forms complexes with hTERT enhancing telomerase activity. Mol Oncol 2016; 10(7): 1086-98.
[54]
Jeong YY, Her J, Oh SY, Chung IK. Hsp90-binding immunophilin FKBP52 modulates telomerase activity by promoting the cytoplasmic retrotransport of hTERT. Biochem J 2016; 473(20): 3517-32.
[55]
Galigniana MD, Echeverria PC, Erlejman AG, Piwien-Pilipuk G. Role of molecular chaperones and TPR-domain proteins in the cytoplasmic transport of steroid receptors and their passage through the nuclear pore. Nucleus 2010; 1(4): 299-308.
[56]
Mazaira GI, Lagadari M, Erlejman AG, Galigniana MD. The emerging role of TPR-domain immunophilins in the mechanism of action of steroid receptors. Nucl Receptor Res 2014; 1(101094): 1-17.
[57]
Galigniana MD, Radanyi C, Renoir JM, Housley PR, Pratt WB. Evidence that the peptidylprolyl isomerase domain of the hsp90-binding immunophilin FKBP52 is involved in both dynein interaction and glucocorticoid receptor movement to the nucleus. J Biol Chem 2001; 276(18): 14884-9.
[58]
Gallo LI, Ghini AA, Piwien Pilipuk G, Galigniana MD. Differential recruitment of tetratricorpeptide repeat domain immunophilins to the mineralocorticoid receptor influences both heat-shock protein 90-dependent retrotransport and hormone-dependent transcriptional activity. Biochemistry 2007; 46(49): 14044-57.
[59]
Galigniana MD, Harrell JM, Murphy PJ, et al. Binding of hsp90-associated immunophilins to cytoplasmic dynein: Direct binding and in vivo evidence that the peptidylprolyl isomerase domain is a dynein interaction domain. Biochemistry 2002; 41(46): 13602-10.
[60]
Pratt WB, Galigniana MD, Harrell JM, DeFranco DB. Role of hsp90 and the hsp90-binding immunophilins in signalling protein movement. Cell Signal 2004; 16(8): 857-72.
[61]
Wochnik GM, Ruegg J, Abel GA, Schmidt U, Holsboer F, Rein T. FK506-binding proteins 51 and 52 differentially regulate dynein interaction and nuclear translocation of the glucocorticoid receptor in mammalian cells. J Biol Chem 2005; 280(6): 4609-16.
[62]
Lukic I, Mitic M, Soldatovic I, et al. Accumulation of cytoplasmic glucocorticoid receptor is related to elevation of FKBP5 in lymphocytes of depressed patients. J Mol Neurosci 2015; 55(4): 951-8.
[63]
Davies TH, Ning YM, Sanchez ER. A new first step in activation of steroid receptors: hormone-induced switching of FKBP51 and FKBP52 immunophilins. J Biol Chem 2002; 277(7): 4597-600.
[64]
Galigniana MD, Erlejman AG, Monte M, Gomez-Sanchez C, Piwien-Pilipuk G. The hsp90-FKBP52 complex links the mineralocorticoid receptor to motor proteins and persists bound to the receptor in early nuclear events. Mol Cell Biol 2010; 30(5): 1285-98.
[65]
Echeverria PC, Mazaira G, Erlejman A, Gomez-Sanchez C, Pilipuk GP, Galigniana MD. Nuclear import of the glucocorticoid receptor-hsp90 complex through the nuclear pore complex is mediated by its interaction with Nup62 and importin beta. Mol Cell Biol 2009; 29(17): 4788-97.
[66]
Grossmann C, Ruhs S, Langenbruch L, et al. Nuclear shuttling precedes dimerization in mineralocorticoid receptor signaling. Chem Biol 2012; 19(6): 742-51.
[67]
Presman DM, Alvarez LD, Levi V, et al. Insights on glucocorticoid receptor activity modulation through the binding of rigid steroids. PloS One 2010; 5(10) e13279
[68]
van Royen ME, van Cappellen WA, de Vos C, Houtsmuller AB, Trapman J. Stepwise androgen receptor dimerization. J Cell Sci 2012; 125(Pt 8): 1970-9.
[69]
Echeverria PC, Picard D. Molecular chaperones, essential partners of steroid hormone receptors for activity and mobility. Biochim Biophys Acta 2010; 1803(6): 641-9.
[70]
Ebong IO, Beilsten-Edmands V, Patel NA, Morgner N, Robinson CV. The interchange of immunophilins leads to parallel pathways and different intermediates in the assembly of Hsp90 glucocorticoid receptor complexes. Cell Discov 2016; 2: 16002.
[71]
Vandevyver S, Dejager L, Libert C. On the trail of the glucocorticoid receptor: Into the nucleus and back. Traffic 2012; 13(3): 364-74.
[72]
Tatro ET, Everall IP, Kaul M, Achim CL. Modulation of glucocorticoid receptor nuclear translocation in neurons by immunophilins FKBP51 and FKBP52: Implications for major depressive disorder. Brain Res 2009; 1286: 1-12.
[73]
Vafopoulou X, Steel CG. Cytoplasmic travels of the ecdysteroid receptor in target cells: Pathways for both genomic and non-genomic actions. Front Endocrinol 2012; 3: 43.
[74]
Schuster M, Schnell L, Feigl P, et al. The Hsp90 machinery facilitates the transport of diphtheria toxin into human cells. Sci Reports 2017; 7(1): 613.
[75]
Galigniana MD, Harrell JM, O’Hagen HM, Ljungman M, Pratt WB. Hsp90-binding immunophilins link p53 to dynein during p53 transport to the nucleus. J Biol Chem 2004; 279(21): 22483-9.
[76]
Colo GP, Rubio MF, Nojek IM, et al. The p160 nuclear receptor co-activator RAC3 exerts an anti-apoptotic role through a cytoplasmatic action. Oncogene 2008; 27(17): 2430-44.
[77]
Harrell JM, Kurek I, Breiman A, et al. All of the protein interactions that link steroid receptor.hsp90.immunophilin heterocomplexes to cytoplasmic dynein are common to plant and animal cells. Biochemistry 2002; 41(17): 5581-7.
[78]
Pratt WB, Krishna P, Olsen LJ. Hsp90-binding immunophilins in plants: The protein movers. Trends Plant Sci 2001; 6(2): 54-8.
[79]
Scammell JG, Denny WB, Valentine DL, Smith DF. Overexpression of the FK506-binding immunophilin FKBP51 is the common cause of glucocorticoid resistance in three New World primates. General Compar Endocrinol 2001; 124(2): 152-65.
[80]
Binder EB, Salyakina D, Lichtner P, et al. Polymorphisms in FKBP5 are associated with increased recurrence of depressive episodes and rapid response to antidepressant treatment. Nat Genet 2004; 36(12): 1319-25.
[81]
Zannas AS, Wiechmann T, Gassen NC, Binder EB. Gene-stress-epigenetic regulation of FKBP5: Clinical and translational implications. Neuropsychopharmacology 2016; 41(1): 261-74.
[82]
Riggs DL, Roberts PJ, Chirillo SC, et al. The Hsp90-binding peptidylprolyl isomerase FKBP52 potentiates glucocorticoid signaling in vivo. EMBO J 2003; 22(5): 1158-67.
[83]
Ward BK, Mark PJ, Ingram DM, Minchin RF, Ratajczak T. Expression of the estrogen receptor-associated immunophilins, cyclophilin 40 and FKBP52, in breast cancer. Breast Cancer Res Treat 1999; 58(3): 267-80.
[84]
Gougelet A, Bouclier C, Marsaud V, et al. Estrogen receptor alpha and beta subtype expression and transactivation capacity are differentially affected by receptor-, hsp90- and immunophilin-ligands in human breast cancer cells. J Steroid Biochem Mol Biol 2005; 94(1-3): 71-81.
[85]
Donley C, McClelland K, McKeen HD, et al. Identification of RBCK1 as a novel regulator of FKBPL: implications for tumor growth and response to tamoxifen. Oncogene 2014; 33(26): 3441-50.
[86]
Nelson L, McKeen HD, Marshall A, et al. FKBPL: a marker of good prognosis in breast cancer. Oncotarget 2015; 6(14): 12209-23.
[87]
Somai S, Chaouat M, Jacob D, et al. Antiestrogens are pro-apoptotic in normal human breast epithelial cells. Int J Cancer 2003; 105(5): 607-12.
[88]
Jordan VC. Antiestrogens and selective estrogen receptor modulators as multifunctional medicines. Clinical considerations and new agents. J Med Chem 2003; 46(7): 1081-111.
[89]
Thomas C, Gustafsson JA. The different roles of ER subtypes in cancer biology and therapy. Nat Rev Cancer 2011; 11(8): 597-608.
[90]
McPherson SJ, Hussain S, Balanathan P, et al. Estrogen receptor-beta activated apoptosis in benign hyperplasia and cancer of the prostate is androgen independent and TNF alpha mediated. Proc Nat Acad Sci USA 2010; 107(7): 3123-8.
[91]
Mak P, Leav I, Pursell B, et al. ERbeta impedes prostate cancer EMT by destabilizing HIF-1alpha and inhibiting VEGF-mediated snail nuclear localization: Implications for Gleason grading. Cancer Cell 2010; 17(4): 319-32.
[92]
Yang Z, Wolf IM, Chen H, et al. FK506-binding protein 52 is essential to uterine reproductive physiology controlled by the progesterone receptor A isoform. Mol Endocrinol 2006; 20(11): 2682-94.
[93]
Tranguch S, Cheung-Flynn J, Daikoku T, et al. Cochaperone immunophilin FKBP52 is critical to uterine receptivity for embryo implantation. Proc Nat Acad Sci USA 2005; 102: 14326-31.
[94]
Tranguch S, Smith DF, Dey SK. Progesterone receptor requires a co-chaperone for signalling in uterine biology and implantation. Reproduct Biomed Online 2006; 13(5): 651-60.
[95]
Periyasamy S, Warrier M, Tillekeratne MP, Shou W, Sanchez ER. The immunophilin ligands cyclosporin A and FK506 suppress prostate cancer cell growth by androgen receptor-dependent and -independent mechanisms. Endocrinology 2007; 148(10): 4716-26.
[96]
Lin JF, Xu J, Tian HY, et al. Identification of candidate prostate cancer biomarkers in prostate needle biopsy specimens using proteomic analysis. Int J Cancer 2007; 121(12): 2596-605.
[97]
Mostaghel EA, Page ST, Lin DW, et al. Intraprostatic androgens and androgen-regulated gene expression persist after testosterone suppression: Therapeutic implications for castration-resistant prostate cancer. Cancer Res 2007; 67(10): 5033-41.
[98]
Periyasamy S, Hinds T Jr, Shemshedini L, Shou W, Sanchez ER. FKBP51 and Cyp40 are positive regulators of androgen-dependent prostate cancer cell growth and the targets of FK506 and cyclosporin A. Oncogene 2010; 29(11): 1691-701.
[99]
Sahu B, Laakso M, Pihlajamaa P, et al. FoxA1 specifies unique androgen and glucocorticoid receptor binding events in prostate cancer cells. Cancer Res 2013; 73(5): 1570-80.
[100]
Kach J, Conzen SD, Szmulewitz RZ. Targeting the glucocorticoid receptor in breast and prostate cancers. Sci Translat Med 2015; 7(305): 305ps19.
[101]
Ni L, Yang CS, Gioeli D, Frierson H, Toft DO, Paschal BM. FKBP51 promotes assembly of the Hsp90 chaperone complex and regulates androgen receptor signaling in prostate cancer cells. Mol Cell Biol 2010; 30(5): 1243-53.
[102]
Solassol J, Mange A, Maudelonde T. FKBP family proteins as promising new biomarkers for cancer. Curr Opin Pharmacol 2011; 11(4): 320-5.
[103]
Russo D, Merolla F, Mascolo M, et al. FKBP51 immunohistochemical expression: A new prognostic biomarker for OSCC? Int J Mol Sci 2017; 18(2)E443
[104]
Huang SL, Chao CC. Silencing of taxol-sensitizer genes in cancer cells: Lack of sensitization effects. Cancers 2015; 7(2): 1052-71.
[105]
Rotoli D, Morales M, Del Carmen Maeso M, et al. Expression and localization of the immunophilin FKBP51 in colorectal carcinomas and primary metastases, and alterations following oxaliplatin-based chemotherapy. Oncol Lett 2016; 12(2): 1315-22.
[106]
Rotoli D, Morales M, Avila J, et al. Commitment of scaffold proteins in the onco-biology of human colorectal cancer and liver metastases after oxaliplatin-based chemotherapy. Int J Mol Sci 2017; 18(4)E891
[107]
Pei H, Li L, Fridley BL, et al. FKBP51 affects cancer cell response to chemotherapy by negatively regulating Akt. Cancer Cell 2009; 16(3): 259-66.
[108]
Romano S, D’Angelillo A, Pacelli R, et al. Role of FK506-binding protein 51 in the control of apoptosis of irradiated melanoma cells. Cell Death Differ 2010; 17(1): 145-57.
[109]
Wang L. FKBP51 regulation of AKT/protein kinase B phosphorylation. Curr Opin Pharmacol 2011; 11(4): 360-4.
[110]
Dogan F, Biray Avci C. Correlation between telomerase and mTOR pathway in cancer stem cells. Gene 2018; 641: 235-9.
[111]
Hausch F, Kozany C, Theodoropoulou M, Fabian AK. FKBPs and the Akt/mTOR pathway. Cell Cycle 2013; 12(15): 2366-70.
[112]
Baretic D, Williams RL. The structural basis for mTOR function. Semin Cell Develop Biol 2014; 36: 91-101.
[113]
Romano S, Sorrentino A, Di Pace AL, Nappo G, Mercogliano C, Romano MF. The emerging role of large immunophilin FK506 binding protein 51 in cancer. Curr Med Chem 2011; 18(35): 5424-9.
[114]
Zaytseva YY, Valentino JD, Gulhati P, Evers BM. mTOR inhibitors in cancer therapy. Cancer Lett 2012; 319(1): 1-7.
[115]
Liu J, Li HQ, Zhou FX, Yu JW, Sun L, Han ZH. Targeting the mTOR pathway in breast cancer. Tumour Biol 2017; 39(6) 1010428317710825
[116]
Akiyama T, Shiraishi T, Qin J, et al. Mitochondria-nucleus shuttling FK506-binding protein 51 interacts with TRAF proteins and facilitates the RIG-I-like receptor-mediated expression of type I IFN. PloS One 2014; 9(5)e95992
[117]
Volkers M, Rohde D, Goodman C, Most P. S100A1: A regulator of striated muscle sarcoplasmic reticulum Ca2+ handling, sarcomeric, and mitochondrial function. J Biomed Biotechnol 2010; 2010 178614
[119]
Holt SE, Aisner DL, Baur J, et al. Functional requirement of p23 and Hsp90 in telomerase complexes. Genes Develop 1999; 13(7): 817-26.
[120]
Gaali S, Kirschner A, Cuboni S, et al. Selective inhibitors of the FK506-binding protein 51 by induced fit. Nat Chem Biol 2015; 11(1): 33-7.
[121]
Napetschnig J, Wu H. Molecular basis of NF-kappaB signaling. Annu Rev Biophys 2013; 42: 443-68.
[122]
Romano S, Mallardo M, Romano MF. FKBP51 and the NF-kappaB regulatory pathway in cancer. Curr Opin Pharmacol 2011; 11(4): 288-93.
[123]
Hoesel B, Schmid JA. The complexity of NF-kappaB signaling in inflammation and cancer. Mol Cancer 2013; 12: 86.
[124]
White DW, Pitoc GA, Gilmore TD. Interaction of the v-Rel oncoprotein with NF-kappaB and IkappaB proteins: Heterodimers of a transformation-defective v-Rel mutant and NF-2 are functional in vitro and in vivo. Mol Cell Biol 1996; 16(3): 1169-78.
[125]
Gilmore TD, Cormier C, Jean-Jacques J, Gapuzan ME. Malignant transformation of primary chicken spleen cells by human transcription factor c-Rel. Oncogene 2001; 20(48): 7098-103.
[126]
Huang Y, Chen R, Zhou J. E2F1 and NF-kappaB: Key mediators of inflammation-associated cancers and potential therapeutic targets. Curr Cancer Drug Targets 2016; 16(9): 765-72.
[127]
Naugler WE, Karin M. NF-kappaB and cancer-identifying targets and mechanisms. Curr Opin Genet Develop 2008; 18(1): 19-26.
[128]
Lagadari M, De Leo SA, Camisay MF, Galigniana MD, Erlejman AG. Regulation of NF-kappaB signalling cascade by immunophilins. Curr Mol Pharmacol 2015; 9(2): 99-108.
[129]
Galigniana NM, Ballmer LT, Toneatto J, Erlejman AG, Lagadari M, Galigniana MD. Regulation of the glucocorticoid response to stress-related disorders by the Hsp90-binding immunophilin FKBP51. J Neurochem 2012; 122(1): 4-18.
[130]
O’Leary JC 3rd, Zhang B, Koren J 3rd, Blair L, Dickey CA. The role of FKBP5 in mood disorders: action of FKBP5 on steroid hormone receptors leads to questions about its evolutionary importance. CNS Neurol Disord Drug Targets 2013; 12(8): 1157-62.
[131]
McKeen HD, McAlpine K, Valentine A, et al. A novel FK506-like binding protein interacts with the glucocorticoid receptor and regulates steroid receptor signaling. Endocrinology 2008; 149(11): 5724-34.
[132]
Wu D, Tao X, Chen ZP, et al. The environmental endocrine disruptor p-nitrophenol interacts with FKBP51, a positive regulator of androgen receptor and inhibits androgen receptor signaling in human cells. J Hazard Mater 2016; 307: 193-201.
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