Received date: 26 Sep 2015
Accepted date: 17 Nov 2015
Published date: 26 Jan 2016
Copyright
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.
Key words: adaptor protein; p66Shc; anoikis; metastasis; autophagy
Yanan Sun , Jie Yang , Zhenyi Ma . Functions of the adaptor protein p66Shc in solid tumors[J]. Frontiers in Biology, 2015 , 10(6) : 487 -494 . DOI: 10.1007/s11515-015-1376-9
1 |
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
|
2 |
Alam S M, Rajendran M, Ouyang S, Veeramani S, Zhang L, Lin M F (2009). A novel role of Shc adaptor proteins in steroid hormone-regulated cancers. Endocr Relat Cancer, 16(1): 1–16
|
3 |
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
|
4 |
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
|
5 |
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
|
6 |
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
|
7 |
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
|
8 |
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
|
9 |
Chen X, Yang C S (2001). Esophageal adenocarcinoma: a review and perspectives on the mechanism of carcinogenesis and chemoprevention. Carcinogenesis, 22(8): 1119–1129
|
10 |
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
|
11 |
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
|
12 |
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
|
13 |
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
|
14 |
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 age-related endothelial dysfunction. Circulation, 110(18): 2889–2895
|
15 |
Frisch S M, Francis H (1994). Disruption of epithelial cell-matrix interactions induces apoptosis. J Cell Biol, 124(4): 619–626
|
16 |
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
|
17 |
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
|
18 |
Gilmore A P (2005). Anoikis. Cell Death Differ, 12(Suppl 2): 1473–1477
|
19 |
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
|
20 |
Grossman S R, Lyle S, Resnick M B, Sabo E, Lis R T, Rosinha E, Liu Q, Hsieh C C, Bhat G, Frackelton A R Jr, 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
|
21 |
Guertin D A, Sabatini D M (2007). Defining the role of mTOR in cancer. Cancer Cell, 12(1): 9–22
|
22 |
Henderson B E, Feigelson H S (2000). Hormonal carcinogenesis. Carcinogenesis, 21(3): 427–433
|
23 |
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
|
24 |
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
|
25 |
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
|
26 |
Lee M S, 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
|
27 |
Levine B (2006). Unraveling the role of autophagy in cancer. Autophagy, 2(2): 65–66
|
28 |
Levine B (2007). Cell biology: autophagy and cancer. Nature, 446(7137): 745–747
|
29 |
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
|
30 |
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
|
31 |
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
|
32 |
Lin M F, Lee M S, 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
|
33 |
Lin M F, Meng T C (1996). Tyrosine phosphorylation of a 185 kDa phosphoprotein (pp185) inversely correlates with the cellular activity of human prostatic acid phosphatase. Biochem Biophys Res Commun, 226(1): 206–213
|
34 |
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
|
35 |
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
|
36 |
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
|
37 |
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
|
38 |
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
|
39 |
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
|
40 |
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
|
41 |
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
|
42 |
Mohan N, Banik N L, Ray S K (2011). Combination of N-(4-hydroxyphenyl) retinamide and apigenin suppressed starvation-induced autophagy and promoted apoptosis in malignant neuroblastoma cells. Neurosci Lett, 502(1): 24–29
|
43 |
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
|
44 |
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
|
45 |
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
|
46 |
Nemoto S, Finkel T (2002). Redox regulation of forkhead proteins through a p66shc-dependent signaling pathway. Science, 295(5564): 2450–2452
|
47 |
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
|
48 |
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
|
49 |
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
|
50 |
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
|
51 |
Pelicci G, Giordano S, Zhen Z, Salcini A E, Lanfrancone L, Bardelli A, Panayotou G, Waterfield M D, Ponzetto C, Pelicci P G,
|
52 |
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
|
53 |
Pellegrini M, Pacini S, Baldari C T (2005). p66SHC: the apoptotic side of Shc proteins. Apoptosis, 10(1): 13–18
|
54 |
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
|
55 |
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
|
56 |
Shen N, Tsao B P (2004). Current advances in the human lupus genetics. Curr Rheumatol Rep, 6(5): 391–398
|
57 |
Stevenson L E, Frackelton A R Jr (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
|
58 |
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
|
59 |
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
|
60 |
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
|
61 |
Veeramani S, Chou Y W, Lin F C, Muniyan S, Lin F F, Kumar S, Xie Y, Lele S M, Tu Y, Lin M F (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
|
62 |
Veeramani S, Igawa T, Yuan T C, Lin F F, Lee M S, 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
|
63 |
Veeramani S, Yuan T C, Chen S J, Lin F F, Petersen J E, Shaheduzzaman S, Srivastava S, MacDonald R G, Lin M F (2005b). Cellular prostatic acid phosphatase: a protein tyrosine phosphatase involved in androgen-independent proliferation of prostate cancer. Endocr Relat Cancer, 12(4): 805–822
|
64 |
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
|
65 |
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
|
66 |
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
|
67 |
Wirawan E, Vanden Berghe T, Lippens S, Agostinis P, Vandenabeele P (2012). Autophagy: for better or for worse. Cell Res, 22(1): 43–61
|
68 |
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
|
69 |
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
|
70 |
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
|
71 |
Yoo B H, Wu X, Li Y, Haniff M, Sasazuki T, Shirasawa S, Eskelinen E L, Rosen K V (2010). Oncogenic ras-induced down-regulation of autophagy mediator Beclin-1 is required for malignant transformation of intestinal epithelial cells. J Biol Chem, 285(8): 5438–5449
|
72 |
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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