Abstract
The mitogen-activated protein kinase (MAPK) and PI3K pathways are regulated by extensive crosstalk, occurring at different levels. In tumors, transactivation of the alternate pathway is a frequent “escape” mechanism, suggesting that combined inhibition of both pathways may achieve synergistic antitumor activity. Here we show that, in the M14 melanoma model, simultaneous inhibition of both MEK and mammalian target of rapamycin (mTOR) achieves synergistic effects at suboptimal concentrations, but becomes frankly antagonistic in the presence of relatively high concentrations of MEK inhibitors. This observation led to the identification of a novel crosstalk mechanism, by which either pharmacologic or genetic inhibition of constitutive MEK signaling restores phosphatase and tensin homolog (PTEN) expression, both in vitro and in vivo, and inhibits downstream signaling through AKT and mTOR, thus bypassing the need for double pathway blockade. This appears to be a general regulatory mechanism and is mediated by multiple mechanisms, such as MAPK-dependent c-Jun and miR-25 regulation. Finally, PTEN upregulation appears to be a major effector of MEK inhibitors’ antitumor activity, as cancer cells in which PTEN is inactivated are consistently more resistant to the growth inhibitory and anti-angiogenic effects of MEK blockade.
Similar content being viewed by others
References
Martin GS (2003) Cell signaling and cancer. Cancer Cell 4:167–174
Milella M, Ciuffreda L, Bria E (2009) Signal transduction pathways as therapeutic targets in cancer therapy. 37: 83
Guertin DA, Sabatini DM (2007) Defining the role of mTOR in cancer. Cancer Cell 12:9–22
Ciuffreda L, McCubrey JA, Milella M (2009) Signaling intermediates (PI3K/PTEN/AKT/mTOR and RAF/MEK/ERK pathways) as therapeutic targets for anti-cancer and anti angiogenesis treatments. Curr Signal Transduct Ther 4:130–143
Engelman JA, Chen L, Tan X, Crosby K, Guimaraes AR, Upadhyay R, Maira M, McNamara K, Perera SA, Song Y et al (2008) Effective use of PI3K and MEK inhibitors to treat mutant Kras G12D and PIK3CA H1047R murine lung cancers. Nat Med 14:1351–1356
Kinkade CW, Castillo-Martin M, Puzio-Kuter A, Yan J, Foster TH, Gao H, Sun Y, Ouyang X, Gerald WL, Cordon-Cardo C et al (2008) Targeting AKT/mTOR and ERK MAPK signaling inhibits hormone-refractory prostate cancer in a preclinical mouse model. J Clin Invest 118:3051–3064
Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, Teague J, Woffendin H, Garnett MJ, Bottomley W et al (2002) Mutations of the BRAF gene in human cancer. Nature 417:949–954
Solit DB, Garraway LA, Pratilas CA, Sawai A, Getz G, Basso A, Ye Q, Lobo JM, She Y, Osman I et al (2006) BRAF mutation predicts sensitivity to MEK inhibition. Nature 439:358–362
Ciuffreda L, Del BD, Desideri M, Di SC, Stoppacciaro A, Ricciardi MR, Chiaretti S, Tavolaro S, Benassi B, Bellacosa A et al (2009) Growth-inhibitory and antiangiogenic activity of the MEK inhibitor PD0325901 in malignant melanoma with or without BRAF mutations. Neoplasia 11:720–731
Robertson GP, Herbst RA, Nagane M, Huang HJ, Cavenee WK (1999) The chromosome 10 monosomy common in human melanomas results from loss of two separate tumor suppressor loci. Cancer Res 59:3596–3601
Dankort D, Curley DP, Cartlidge RA, Nelson B, Karnezis AN, Damsky WE Jr, You MJ, DePinho RA, McMahon M, Bosenberg M (2009) BrafV600E cooperates with Pten loss to induce metastatic melanoma. Nat Genet 41:544–552
Eramo A, Lotti F, Sette G, Pilozzi E, Biffoni M, Di VA, Conticello C, Ruco L, Peschle C, De MR (2008) Identification and expansion of the tumorigenic lung cancer stem cell population. Cell Death Differ 15:504–514
Milella M, Trisciuoglio D, Bruno T, Ciuffreda L, Mottolese M, Cianciulli A, Cognetti F, Zangemeister-Wittke U, Del Bufalo D, Zupi G (2004) Trastuzumab down-regulates Bcl-2 expression and potentiates apoptosis induction by Bcl-2/Bcl-XL bispecific antisense oligonucleotides in HER-2 gene–amplified breast cancer cells. Clin Cancer Res 10:7747–7756
Hettinger K, Vikhanskaya F, Poh MK, Lee MK, de Belle I, Zhang JT, Reddy SA, Sabapathy K (2007) c-Jun promotes cellular survival by suppression of PTEN. Cell Death Differ 14:218–229
von Gise A, Lorenz P, Wellbrock C, Hemmings B, Berberich-Siebelt F, Rapp UR, Troppmair J (2001) Apoptosis suppression by Raf-1 and MEK1 requires MEK- and phosphatidylinositol 3-kinase-dependent signals. Mol Cell Biol 21:2324–2336
Lopez-Bergami P, Huang C, Goydos JS, Yip D, Bar-Eli M, Herlyn M, Smalley KS, Mahale A, Eroshkin A, Aaronson S et al (2007) Rewired ERK-JNK signaling pathways in melanoma. Cancer Cell 11:447–460
Robinson MJ, Stippec SA, Goldsmith E, White MA, Cobb MH (1998) A constitutively active and nuclear form of the MAP kinase ERK2 is sufficient for neurite outgrowth and cell transformation. Curr Biol 8:1141–1150
Leslie NR, Gray A, Pass I, Orchiston EA, Downes CP (2000) Analysis of the cellular functions of PTEN using catalytic domain and C-terminal mutations: differential effects of C-terminal deletion on signalling pathways downstream of phosphoinositide 3-kinase. Biochem J 346(Pt 3):827–833
Pisano C, De CM, Beretta GL, Zuco V, Pratesi G, Penco S, Vesci L, Fodera R, Ferrara FF, Guglielmi MB et al (2008) Preclinical profile of antitumor activity of a novel hydrophilic camptothecin, ST1968. Mol Cancer Ther 7:2051–2059
Chou TC, Talalay P (1984) Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors. Adv Enzyme Regul 22:27–55
Vasudevan KM, Burikhanov R, Goswami A, Rangnekar VM (2007) Suppression of PTEN expression is essential for antiapoptosis and cellular transformation by oncogenic Ras. Cancer Res 67:10343–10350
Poliseno L, Salmena L, Zhang J, Carver B, Haveman WJ, Pandolfi PP (2010) A coding-independent function of gene and pseudogene mRNAs regulates tumour biology. Nature 465:1033–1038
Poliseno L, Salmena L, Riccardi L, Fornari A, Song MS, Hobbs RM, Sportoletti P, Varmeh S, Egia A, Fedele G et al (2010) Identification of the miR-106b~25 microRNA cluster as a proto-oncogenic PTEN-targeting intron that cooperates with its host gene MCM7 in transformation. Sci Signal 3:ra29
Ming M, Han W, Maddox J, Soltani K, Shea CR, Freeman DM, He YY (2010) UVB-induced ERK/AKT-dependent PTEN suppression promotes survival of epidermal keratinocytes. Oncogene 29:492–502
Wei W, Jin J, Schlisio S, Harper JW, Kaelin WG Jr (2005) The v-Jun point mutation allows c-Jun to escape GSK3-dependent recognition and destruction by the Fbw7 ubiquitin ligase. Cancer Cell 8:25–33
Bain J, Plater L, Elliott M, Shpiro N, Hastie CJ, McLauchlan H, Klevernic I, Arthur JS, Alessi DR, Cohen P (2007) The selectivity of protein kinase inhibitors: a further update. Biochem J 408:297–315
Jiang BH, Liu LZ (2009) PI3K/PTEN signaling in angiogenesis and tumorigenesis. Adv Cancer Res 102:19–65
Kwabi-Addo B, Giri D, Schmidt K, Podsypanina K, Parsons R, Greenberg N, Ittmann M (2001) Haploinsufficiency of the Pten tumor suppressor gene promotes prostate cancer progression. Proc Natl Acad Sci U S A 98:11563–11568
Leslie NR, Downes CP (2004) PTEN function: how normal cells control it and tumour cells lose it. Biochem J 382:1–11
Trotman LC, Niki M, Dotan ZA, Koutcher JA, Di CA, Xiao A, Khoo AS, Roy-Burman P, Greenberg NM, Van DT et al (2003) Pten dose dictates cancer progression in the prostate. PLoS Biol 1:E59
Ming M, He YY (2009) PTEN: new insights into its regulation and function in skin cancer. J Invest Dermatol 129:2109–2112
Tsao H, Zhang X, Benoit E, Haluska FG (1998) Identification of PTEN/MMAC1 alterations in uncultured melanomas and melanoma cell lines. Oncogene 16:3397–3402
Stahl JM, Sharma A, Cheung M, Zimmerman M, Cheng JQ, Bosenberg MW, Kester M, Sandirasegarane L, Robertson GP (2004) Deregulated Akt3 activity promotes development of malignant melanoma. Cancer Res 64:7002–7010
Lin WM, Baker AC, Beroukhim R, Winckler W, Feng W, Marmion JM, Laine E, Greulich H, Tseng H, Gates C et al (2008) Modeling genomic diversity and tumor dependency in malignant melanoma. Cancer Res 68:664–673
Tsao H, Goel V, Wu H, Yang G, Haluska FG (2004) Genetic interaction between NRAS and BRAF mutations and PTEN/MMAC1 inactivation in melanoma. J Invest Dermatol 122:337–341
Wee S, Jagani Z, Xiang KX, Loo A, Dorsch M, Yao YM, Sellers WR, Lengauer C, Stegmeier F (2009) PI3K pathway activation mediates resistance to MEK inhibitors in KRAS mutant cancers. Cancer Res 69:4286–4293
Gopal YN, Deng W, Woodman SE, Komurov K, Ram P, Smith PD, Davies MA (2010) Basal and treatment-induced activation of AKT mediates resistance to cell death by AZD6244 (ARRY-142886) in Braf-mutant human cutaneous melanoma cells. Cancer Res 70:8736–8747
Acknowledgments
This work was supported in part by grants from the Italian Association for Cancer Research (AIRC), the Cariplo Foundation, and the Italian Ministry of Health.
Author information
Authors and Affiliations
Corresponding author
Electronic supplementary material
Below is the link to the electronic supplementary material.
ESM 1
PDF 123 kb
Rights and permissions
About this article
Cite this article
Ciuffreda, L., Di Sanza, C., Cesta Incani, U. et al. The mitogen-activated protein kinase (MAPK) cascade controls phosphatase and tensin homolog (PTEN) expression through multiple mechanisms. J Mol Med 90, 667–679 (2012). https://doi.org/10.1007/s00109-011-0844-1
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00109-011-0844-1