Transcriptional regulation and functional implication of S100P in cancer
- 738 Downloads
S100P is an EF-hand calcium-binding protein that was originally identified in placenta and subsequently associated with cancer. It is a member of S100 family of proteins that function as extracellular and/or intracellular regulators of diverse cellular processes and participate in various human pathologies. S100P expression was detected in a spectrum of human tumor cell lines and tissues derived from breast, prostate, pancreas, lung and colon, where it was connected with malignant phenotype, hormone independence and resistance to chemotherapy. Overexpression of S100P was shown to promote tumorigenesis and metastasis in diverse cancer models. Functional studies of S100P indicate that its biological activities are exerted through extracellular signaling via RAGE receptor, resulting in increased proliferation and survival, or through intracellular interaction with ezrin, leading to increased cell migration and metastasis. Molecular mechanisms regulating expression of S100P in cancer cells are just emerging. Besides earlier described DNA methylation, recent studies implicate bone morphogenic protein and non-steroidal anti-inflammatory drugs in control of S100P expression during tumor progression. Functional analysis of S100P promoter identified SMAD, STAT/CREB and SP/KLF binding sites as key regulatory elements participating in transcriptional activation of S100P gene in cancer cells. Moreover, the most recent data reveal that expression of S100P is up-regulated by activation of glucocorticoid receptor suggesting that S100P could play a role in therapy resistance mediated by glucocorticoids in solid tumors. Elucidation of S100P regulation is an important step towards understanding biological significance of its tissue distribution and proposing strategies for targeted S100P modulation.
KeywordsS100P Calcium-binding protein Transcriptional regulation Cancer
The research of the authors is supported by the Slovak Scientific Grant Agency (VEGA 2/0143/08).
- Amler LC, Agus DB, LeDuc C, Sapinoso ML, Fox WD, Kern S, Lee D, Wang V, Leysens M, Higgins B, Martin J, Gerald W, Dracopoli N, Cordon-Cardo C, Scher HI, Hampton GM (2000) Dysregulated expression of androgen-responsive and nonresponsive genes in the androgen-independent prostate cancer xenograft model CWR22-R1. Cancer Res 60:6134–6141PubMedGoogle Scholar
- Bertram J, Palfner K, Hiddemann W, Kneba M (1998) Elevated expression of S100P, CAPL and MAGE 3 in doxorubicin-resistant cell lines: comparison of mRNA differential display reverse transcription-polymerase chain reaction and subtractive suppressive hybridization for the analysis of differential gene expression. Anticancer Drugs 9:311–317PubMedCrossRefGoogle Scholar
- Bray JD, Jelinsky S, Ghatge R, Bray JA, Tunkey C, Saraf K, Jacobsen BM, Richer JK, Brown EL, Winneker RC, Horwitz KB, Lyttle CR (2005) Quantitative analysis of gene regulation by seven clinically relevant progestins suggests a highly similar mechanism of action through progesterone receptors in T47D breast cancer cells. J Steroid Biochem Mol Biol 97:328–341PubMedCrossRefGoogle Scholar
- Bulk E, Hascher A, Liersch R, Mesters RM, Diederichs S, Sargin B, Gerke V, Hotfilder M, Vormoor J, Berdel WE, Serve H, Muller-Tidow C (2008) Adjuvant therapy with small hairpin RNA interference prevents non-small cell lung cancer metastasis development in mice. Cancer Res 68:1896–1904PubMedCrossRefGoogle Scholar
- Crnogorac-Jurcevic T, Missiaglia E, Blaveri E, Gangeswaran R, Jones M, Terris B, Costello E, Neoptolemos JP, Lemoine NR (2003) Molecular alterations in pancreatic carcinoma: expression profiling shows that dysregulated expression of S100 genes is highly prevalent. J Pathol 201:63–74PubMedCrossRefGoogle Scholar
- Diederichs S, Bulk E, Steffen B, Ji P, Tickenbrock L, Lang K, Zanker KS, Metzger R, Schneider PM, Gerke V, Thomas M, Berdel WE, Serve H, Muller-Tidow C (2004) S100 family members and trypsinogens are predictors of distant metastasis and survival in early-stage non-small cell lung cancer. Cancer Res 64:5564–5569PubMedCrossRefGoogle Scholar
- Guerreiro Da Silva ID, Hu YF, Russo IH, Ao X, Salicioni AM, Yang X, Russo J (2000) S100P calcium-binding protein overexpression is associated with immortalization of human breast epithelial cells in vitro and early stages of breast cancer development in vivo. Int J Oncol 16:231–240PubMedGoogle Scholar
- Hamada S, Satoh K, Hirota M, Fujibuchi W, Kanno A, Umino J, Ito H, Satoh A, Kikuta K, Kume K, Masamune A, Shimosegawa T (2009) Expression of the calcium-binding protein S100P is regulated by bone morphogenetic protein in pancreatic duct epithelial cell lines. Cancer Sci 100:103–110PubMedCrossRefGoogle Scholar
- Mousses S, Wagner U, Chen Y, Kim JW, Bubendorf L, Bittner M, Pretlow T, Elkahloun AG, Trepel JB, Kallioniemi OP (2001) Failure of hormone therapy in prostate cancer involves systematic restoration of androgen responsive genes and activation of rapamycin sensitive signaling. Oncogene 20:6718–6723PubMedCrossRefGoogle Scholar
- Mousses S, Bubendorf L, Wagner U, Hostetter G, Kononen J, Cornelison R, Goldberger N, Elkahloun AG, Willi N, Koivisto P, Ferhle W, Raffeld M, Sauter G, Kallioniemi OP (2002) Clinical validation of candidate genes associated with prostate cancer progression in the CWR22 model system using tissue microarrays. Cancer Res 62:1256–1260PubMedGoogle Scholar
- Song J, Shih IeM, Chan DW, Zhang Z (2009): Suppression of annexin A11 in ovarian cancer: implications in chemoresistance. Neoplasia 11:605–614, 1 p following 614Google Scholar