Abstract
p66Shc is a 66 kDa Src homology 2 domain containing (Shc) adaptor protein homolog. Previous studies have demonstrated that p66Shc is a proapoptotic protein involved in the cellular response to oxidative stress and in regulating mammalian lifespan. However, accumulating evidence also indicates its critical role in solid tumor progression. The expression of p66Shc varies in different types of solid tumors, and it can paradoxically promote as well as suppress tumor progression, survival, and metastasis, depending on the cellular context. In this review, we discuss its functions in various solid tumors, the mechanisms by which it mediates the process of anoikis (detachment-induced cell death), and the epigenetic mechanisms that regulate its expression. These studies indicate the potential of p66Shc as a novel prognostic marker and therapeutic target for the prevention of tumor progression and metastasis.
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Abdollahi A, Gruver B N, Patriotis C, Hamilton T C (2003). Identification of epidermal growth factor-responsive genes in normal rat ovarian surface epithelial cells. Biochem Biophys Res Commun, 307(1): 188–197
Alam S M, Rajendran M, Ouyang S, Veeramani S, Zhang L, Lin M F (2009). A novel role of Shc adaptor proteins in steroid hormoneregulated cancers. Endocr Relat Cancer, 16(1): 1–16
Almeida M, Han L, Ambrogini E, Bartell S M, Manolagas S C (2010). Oxidative stress stimulates apoptosis and activates NF-kappaB in osteoblastic cells via a PKCbeta/p66shc signaling cascade: counter regulation by estrogens or androgens. Mol Endocrinol, 24(10): 2030–2037
Banerjee P, Basu A, Wegiel B, Otterbein L E, Mizumura K, Gasser M, Waaga-Gasser A M, Choi A M, Pal S (2012). Heme oxygenase-1 promotes survival of renal cancer cells through modulation of apoptosis- and autophagy-regulating molecules. J Biol Chem, 287 (38): 32113–32123
Bhat H F, Baba R A, Adams M E, Khanday F A (2014). Role of SNTA1 in Rac1 activation, modulation of ROS generation, and migratory potential of human breast cancer cells. Br J Cancer, 110(3): 706–714
Borkowska A, Knap N, Antosiewicz J (2013). Diallyl trisulfide is more cytotoxic to prostate cancer cells PC-3 than to noncancerous epithelial cell line PNT1A: a possible role of p66Shc signaling axis. Nutr Cancer, 65(5): 711–717
Brown J E, Zeiger S L, Hettinger J C, Brooks J D, Holt B, Morrow J D, Musiek E S, Milne G, McLaughlin B (2010). Essential role of the redox-sensitive kinase p66shc in determining energetic and oxidative status and cell fate in neuronal preconditioning. J Neurosci, 30(15): 5242–5252
Chen C S, Mrksich M, Huang S, Whitesides G M, Ingber D E (1997). Geometric control of cell life and death. Science, 276(5317): 1425–1428
Chen X, Yang C S (2001). Esophageal adenocarcinoma: a review and perspectives on the mechanism of carcinogenesis and chemoprevention. Carcinogenesis, 22(8): 1119–1129
Deffieu M, Bhatia-Kissová I, Salin B, Galinier A, Manon S, Camougrand N (2009). Glutathione participates in the regulation of mitophagy in yeast. J Biol Chem, 284(22): 14828–14837
Du W, Jiang Y, Zheng Z, Zhang Z, Chen N, Ma Z, Yao Z, Terada L, Liu Z (2013). Feedback loop between p66(Shc) and Nrf2 promotes lung cancer progression. Cancer Lett, 337(1): 58–65
Faisal A, el-Shemerly M, Hess D, Nagamine Y (2002). Serine/threonine phosphorylation of ShcA. Regulation of protein-tyrosine phosphatase- pest binding and involvement in insulin signaling. J Biol Chem, 277(33): 30144–30152
Foschi M, Franchi F, Han J, La Villa G, Sorokin A (2001). Endothelin-1 induces serine phosphorylation of the adaptor protein p66Shc and its association with 14–3-3 protein in glomerular mesangial cells. J Biol Chem, 276(28): 26640–26647
Francia P, delli Gatti C, Bachschmid M, Martin-Padura I, Savoia C, Migliaccio E, Pelicci P G, Schiavoni M, Lüscher T F, Volpe M, Cosentino F (2004). Deletion of p66shc gene protects against agerelated endothelial dysfunction. Circulation, 110(18): 2889–2895
Frisch S M, Francis H (1994). Disruption of epithelial cell-matrix interactions induces apoptosis. J Cell Biol, 124(4): 619–626
Frisch S M, Vuori K, Ruoslahti E, Chan-Hui P Y (1996). Control of adhesion-dependent cell survival by focal adhesion kinase. J Cell Biol, 134(3): 793–799
Galimov E R, Chernyak B V, Sidorenko A S, Tereshkova A V, Chumakov P M (2014). Prooxidant properties of p66shc are mediated by mitochondria in human cells. PLoS ONE, 9(3): e86521
Gilmore A P (2005). Anoikis. Cell Death Differ, 12(Suppl 2): 1473–1477
Giorgio M, Migliaccio E, Orsini F, Paolucci D, Moroni M, Contursi C, Pelliccia G, Luzi L, Minucci S, Marcaccio M, Pinton P, Rizzuto R, Bernardi P, Paolucci F, Pelicci P G (2005). Electron transfer between cytochrome c and p66Shc generates reactive oxygen species that trigger mitochondrial apoptosis. Cell, 122(2): 221–233
Grossman S R, Lyle S, Resnick MB, Sabo E, Lis R T, Rosinha E, Liu Q, Hsieh C C, Bhat G, Frackelton A R, Hafer L J (2007). p66 Shc tumor levels show a strong prognostic correlation with disease outcome in stage IIA colon cancer. Clin Cancer Res, 13(19): 5798–5804
Guertin D A, Sabatini DM(2007). Defining the role of mTOR in cancer. Cancer Cell, 12(1): 9–22
Henderson B E, Feigelson H S (2000). Hormonal carcinogenesis. Carcinogenesis, 21(3): 427–433
Jackson J G, Yoneda T, Clark G M, Yee D (2000). Elevated levels of p66 Shc are found in breast cancer cell lines and primary tumors with high metastatic potential. Clin Cancer Res, 6(3): 1135–1139
Khanday F A, Yamamori T, Mattagajasingh I, Zhang Z, Bugayenko A, Naqvi A, Santhanam L, Nabi N, Kasuno K, Day B W, Irani K (2006). Rac1 leads to phosphorylation-dependent increase in stability of the p66shc adaptor protein: role in Rac1-induced oxidative stress. Mol Biol Cell, 17(1): 122–129
Kilpinen S, Autio R, Ojala K, Iljin K, Bucher E, Sara H, Pisto T, Saarela M, Skotheim R I, Björkman M, Mpindi J P, Haapa-Paananen S, Vainio P, Edgren H, Wolf M, Astola J, Nees M, Hautaniemi S, Kallioniemi O (2008). Systematic bioinformatic analysis of expression levels of 17,330 human genes across 9,783 samples from 175 types of healthy and pathological tissues. Genome Biol, 9(9). R139
Lee MS, Igawa T, Chen S J, Van Bemmel D, Lin J S, Lin F F, Johansson S L, Christman J K, Lin M F (2004). p66Shc protein is upregulated by steroid hormones in hormone-sensitive cancer cells and in primary prostate carcinomas. Int J Cancer, 108(5): 672–678
Levine B (2006). Unraveling the role of autophagy in cancer. Autophagy, 2(2): 65–66
Levine B (2007). Cell biology: autophagy and cancer. Nature, 446 (7137): 745–747
Li X, Gao D, Wang H, Li X, Yang J, Yan X, Liu Z, Ma Z (2015). Negative feedback loop between p66Shc and ZEB1 regulates fibrotic EMT response in lung cancer cells. Cell Death Dis, 6: e1708
Li X, Xu Z, Du W, Zhang Z, Wei Y, Wang H, Zhu Z, Qin L, Wang L, Niu Q, Zhao X, Girard L, Gong Y, Ma Z, Sun B, Yao Z, Minna J D, Terada L S, Liu Z (2014). Aiolos promotes anchorage independence by silencing p66Shc transcription in cancer cells. Cancer Cell, 25(5): 575–589
Li Y, Zhang Q, Tian R, Wang Q, Zhao J J, Iglehart J D, Wang Z C, Richardson A L (2011). Lysosomal transmembrane protein LAPTM4B promotes autophagy and tolerance to metabolic stress in cancer cells. Cancer Res, 71(24). 7481–7489
Lin MF, Lee MS, Zhou X W, Andressen J C, Meng T C, Johansson S L, West W W, Taylor R J, Anderson J R, Lin F F (2001). Decreased expression of cellular prostatic acid phosphatase increases tumorigenicity of human prostate cancer cells. J Urol, 166(5): 1943–1950
Lin M F, Meng T C (1996). Tyrosine phosphorylation of a 185 kDa phosphoprotein (p185) inversely correlates with the cellular activity of human prostatic acid phosphatase. Biochem Biophys Res Commun, 226(1): 206–213
Luzi L, Confalonieri S, Di Fiore P P, Pelicci P G (2000). Evolution of Shc functions from nematode to human. Curr Opin Genet Dev, 10(6): 668–674
Ma Z, Liu Z, Wu R F, Terada L S (2010). p66(Shc) restrains Ras hyperactivation and suppresses metastatic behavior. Oncogene, 29 (41): 5559–5567
Ma Z, Myers D P, Wu R F, Nwariaku F E, Terada L S (2007). p66Shc mediates anoikis through RhoA. J Cell Biol, 179(1): 23–31
Mailleux A A, Overholtzer M, Schmelzle T, Bouillet P, Strasser A, Brugge J S (2007). BIM regulates apoptosis during mammary ductal morphogenesis, and its absence reveals alternative cell death mechanisms. Dev Cell, 12(2): 221–234
Malhotra A, Vashistha H, Yadav V S, Dube M G, Kalra S P, Abdellatif M, Meggs L G (2009). Inhibition of p66ShcA redox activity in cardiac muscle cells attenuates hyperglycemia-induced oxidative stress and apoptosis. Am J Physiol Heart Circ Physiol, 296(2): H380–H388
Martin M J, Melnyk N, Pollard M, Bowden M, Leong H, Podor T J, Gleave M, Sorensen P H (2006). The insulin-like growth factor I receptor is required for Akt activation and suppression of anoikis in cells transformed by the ETV6-NTRK3 chimeric tyrosine kinase. Mol Cell Biol, 26(5): 1754–1769
Migliaccio E, Giorgio M, Mele S, Pelicci G, Reboldi P, Pandolfi P P, Lanfrancone L, Pelicci P G (1999). The p66shc adaptor protein controls oxidative stress response and life span in mammals. Nature, 402(6759): 309–313
Migliaccio E, Mele S, Salcini A E, Pelicci G, Lai K M, Superti-Furga G, Pawson T, Di Fiore P P, Lanfrancone L, Pelicci P G (1997). Opposite effects of the p52shc/p46shc and p66shc splicing isoforms on the EGF receptor-MAP kinase-fos signalling pathway. EMBO J, 16(4): 706–716
Mohan N, Banik N L, Ray S K (2011). Combination of N-(4-hydroxyphenyl) retinamide and apigenin suppressed starvationinduced autophagy and promoted apoptosis in malignant neuroblastoma cells. Neurosci Lett, 502(1): 24–29
Morgan B, Sun L, Avitahl N, Andrikopoulos K, Ikeda T, Gonzales E, Wu P, Neben S, Georgopoulos K (1997). Aiolos, a lymphoid restricted transcription factor that interacts with Ikaros to regulate lymphocyte differentiation. EMBO J, 16(8): 2004–2013
Muniyan S, Chou Y W, Tsai T J, Thomes P, Veeramani S, Benigno B B, Walker L D, McDonald J F, Khan S A, Lin F F, Lele S M, Lin M F (2015). p66Shc longevity protein regulates the proliferation of human ovarian cancer cells. Mol Carcinog, 54(8): 618–631
Napoli C, Martin-Padura I, de Nigris F, Giorgio M, Mansueto G, Somma P, Condorelli M, Sica G, De Rosa G, Pelicci P (2003). Deletion of the p66Shc longevity gene reduces systemic and tissue oxidative stress, vascular cell apoptosis, and early atherogenesis in mice fed a high-fat diet. Proc Natl Acad Sci USA, 100(4): 2112–2116
Nemoto S, Finkel T (2002). Redox regulation of forkhead proteins through a p66shc-dependent signaling pathway. Science, 295(5564): 2450–2452
Nobes C D, Hall A (1995). Rho, rac, and cdc42 GTPases regulate the assembly of multimolecular focal complexes associated with actin stress fibers, lamellipodia, and filopodia. Cell, 81(1): 53–62
Northey J J, Chmielecki J, Ngan E, Russo C, Annis M G, Muller W J, Siegel P M (2008). Signaling through ShcA is required for transforming growth factor beta- and Neu/ErbB-2-induced breast cancer cell motility and invasion. Mol Cell Biol, 28(10): 3162–3176
Orsini F, Migliaccio E, Moroni M, Contursi C, Raker V A, Piccini D, Martin-Padura I, Pelliccia G, Trinei M, Bono M, Puri C, Tacchetti C, Ferrini M, Mannucci R, Nicoletti I, Lanfrancone L, Giorgio M, Pelicci P G (2004). The life span determinant p66Shc localizes to mitochondria where it associates with mitochondrial heat shock protein 70 and regulates trans-membrane potential. J Biol Chem, 279 (24): 25689–25695
Pattingre S, Bauvy C, Codogno P (2003). Amino acids interfere with the ERK1/2-dependent control of macroautophagy by controlling the activation of Raf-1 in human colon cancer HT-29 cells. J Biol Chem, 278(19): 16667–16674
Pelicci G, Giordano S, Zhen Z, Salcini A E, Lanfrancone L, Bardelli A, Panayotou G, Waterfield M D, Ponzetto C, Pelicci P G, et al (1995). The motogenic and mitogenic responses to HGF are amplified by the Shc adaptor protein. Oncogene, 10(8): 1631–1638
Pelicci G, Lanfrancone L, Grignani F, McGlade J, Cavallo F, Forni G, Nicoletti I, Grignani F, Pawson T, Pelicci P G (1992). A novel transforming protein (SHC) with an SH2 domain is implicated in mitogenic signal transduction. Cell, 70(1): 93–104
Pellegrini M, Pacini S, Baldari C T (2005). p66SHC: the apoptotic side of Shc proteins. Apoptosis, 10(1): 13–18
Re F, Zanetti A, Sironi M, Polentarutti N, Lanfrancone L, Dejana E, Colotta F (1994). Inhibition of anchorage-dependent cell spreading triggers apoptosis in cultured human endothelial cells. J Cell Biol, 127(2): 537–546
Sakai H, Igawa T, Saha P K, Nomata K, Yushita Y, Kanetake H, Saito Y (1992). A case of prostatic carcinoma presenting as a metastatic orbital tumor. Hinyokika Kiyo, 38(1): 77–80
Shen N, Tsao B P (2004). Current advances in the human lupus genetics. Curr Rheumatol Rep, 6(5): 391–398
Stevenson L E, Frackelton A R (1998). Constitutively tyrosine phosphorylated p52 Shc in breast cancer cells: correlation with ErbB2 and p66 Shc expression. Breast Cancer Res Treat, 49(2): 119–128
Thompson E C, Cobb B S, Sabbattini P, Meixlsperger S, Parelho V, Liberg D, Taylor B, Dillon N, Georgopoulos K, Jumaa H, Smale S T, Fisher A G, Merkenschlager M(2007). Ikaros DNA-binding proteins as integral components of B cell developmental-stage-specific regulatory circuits. Immunity, 26(3): 335–344
Trinei M, Migliaccio E, Bernardi P, Paolucci F, Pelicci P, Giorgio M (2013). p66Shc, mitochondria, and the generation of reactive oxygen species. Methods Enzymol, 528: 99–110
Varma M, Morgan M, O’Rourke D, Jasani B (2004). Prostate specific antigen (PSA) and prostate specific acid phosphatase (PSAP) immunoreactivity in benign seminal vesicleduct epithelium: a potential pitfall in the diagnosis of prostate cancer in needle biopsy specimens. Histopathology, 44(4): 405–406
Veeramani S, Chou Y W, Lin F C, Muniyan S, Lin F F, Kumar S, Xie Y, Lele S M, Tu Y, LinMF (2012). Reactive oxygen species induced by p66Shc longevity protein mediate nongenomic androgen action via tyrosine phosphorylation signaling to enhance tumorigenicity of prostate cancer cells. Free Radic Biol Med, 53(1): 95–108
Veeramani S, Igawa T, Yuan T C, Lin F F, LeeMS, Lin J S, Johansson S L, Lin M F (2005a). Expression of p66(Shc) protein correlates with proliferation of human prostate cancer cells. Oncogene, 24(48): 7203–7212
Veeramani S, Yuan T C, Chen S J, Lin F F, Petersen J E, Shaheduzzaman S, Srivastava S, MacDonald R G, Lin MF (2005b). Cellular prostatic acid phosphatase: a protein tyrosine phosphatase involved in androgen-independent proliferation of prostate cancer. Endocr Relat Cancer, 12(4): 805–822
Veeramani S, Yuan T C, Lin F F, Lin M F (2008). Mitochondrial redox signaling by p66Shc is involved in regulating androgenic growth stimulation of human prostate cancer cells. Oncogene, 27(37): 5057–5068
Wang J H, Avitahl N, Cariappa A, Friedrich C, Ikeda T, Renold A, Andrikopoulos K, Liang L, Pillai S, Morgan B A, Georgopoulos K (1998). Aiolos regulates B cell activation and maturation to effector state. Immunity, 9(4): 543–553
Webster M A, Hutchinson J N, Rauh M J, Muthuswamy S K, Anton M, Tortorice C G, Cardiff R D, Graham F L, Hassell J A, Muller W J (1998). Requirement for both Shc and phosphatidylinositol 3' kinase signaling pathways in polyomavirus middle T-mediated mammary tumorigenesis. Mol Cell Biol, 18(4): 2344–2359
Wirawan E, Vanden Berghe T, Lippens S, Agostinis P, Vandenabeele P (2012). Autophagy: for better or for worse. Cell Res, 22(1): 43–61
Xiao D, Singh S V (2010). p66Shc is indispensable for phenethyl isothiocyanate-induced apoptosis in human prostate cancer cells. Cancer Res, 70(8): 3150–3158
Xie Y, Hung M C (1996). p66Shc isoform down-regulated and not required for HER-2/neu signaling pathway in human breast cancer cell lines with HER-2/neu overexpression. Biochem Biophys Res Commun, 221(1): 140–145
Yang J, Zheng Z, Yan X, Li X, Liu Z, Ma Z (2013). Integration of autophagy and anoikis resistance in solid tumors. Anat Rec (Hoboken), 296(10): 1501–1508
Yoo B H, Wu X, Li Y, Haniff M, Sasazuki T, Shirasawa S, Eskelinen E L, Rosen K V (2010). Oncogenic ras-induced downregulation of autophagy mediator Beclin-1 is required for malignant transformation of intestinal epithelial cells. J Biol Chem, 285(8): 5438–5449
Zheng Z, Yang J, Zhao D, Gao D, Yan X, Yao Z, Liu Z, Ma Z (2013). Downregulated adaptor protein p66(Shc) mitigates autophagy process by low nutrient and enhances apoptotic resistance in human lung adenocarcinoma A549 cells. FEBS J, 280(18): 4522–4530
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Sun, Y., Yang, J. & Ma, Z. Functions of the adaptor protein p66Shc in solid tumors. Front. Biol. 10, 487–494 (2015). https://doi.org/10.1007/s11515-015-1376-9
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DOI: https://doi.org/10.1007/s11515-015-1376-9