Abstract
Overexpression of the multidrug resistanceMDR1 gene is thought to contribute to drug resistance in non-responsive cancers like colorectal carcinoma. Little is known about the mechanisms by which expression ofMDR1 is regulated in human tumours. However, there is growing evidence that regulation primarily takes place at the transcriptional level and that the process of tumour progression is related to activation of theMDR1 gene. Mutations in thep53 tumour-suppression gene occur in approximately 70% of colorectal cancers. As a transcriptional regulator,p53 might be involved in regulation ofMDR1 expression in these tumours. We therefore determinedMDR1 expression using the differential polymerase chain reaction technique in 30 colorectal tumours (4 primaries and 26 metastates) and correlated our results with previously reported data onp53 in the same group of patients. We found a significant positive correlation betweenp53 andMDR1 expression inp53-mutated tumours (P=0.005;r=0.596), but not in tumours without ap53 mutation. In addition, we observed a tendency towards higherMDR1 expression levels in tumours carryingp53 mutations (P=0.14) compound to wild-typep53 tumours. These data indicate that mutantp53 may play a role in the regulation ofMDR1 expression in human cholorectal cancer.
Key words: p53, MDR1, Colorectal cancer, Metastasis
References
- Baker SJ, Preisinger AC, Jessup JM, Paraskeva C, Markowitz S, Willson JK, Hamilton S, Vogelstein B (1990) p53 gene mutations occur in combination with 17p allelic deletions as late events in colorectal tumourigenesis. Cancer Res 50:7717–7722 [PubMed] [Google Scholar]
- Banerjee S, Ganapathi R, Ghosh L, Yu Cl (1992) Down-regulation ofras andmyc expression associated withmdr-1 overexpression in Adriamycin-resistant tumour cells. Cell Mol Biol 38:561–570 [PubMed] [Google Scholar]
- Burt RK, Garfield S, Johnson K, Thorgeirsson SS (1988). Transformation of rat liver epithelial cells with v-H-ras or v-raf causes expression of MDR-1, glutathione-S-transferase-P and increased resistance to cytotoxic chemicals. Carcinogenesis 9:2329–2332 [DOI] [PubMed] [Google Scholar]
- Chin KV, Ueda K, Pastan I, Gottesman MM (1992) Modulation of activity of the promoter of the humanMDR1 gene by Ras andp53. Science 255:459–462 [DOI] [PubMed] [Google Scholar]
- Cohen AM, Shank B, Friedman MA (1989) Colorectal cancer. In: DeVita Jr VT, Hellman S, Rosenberg S (eds) Cancer: principles and practice of oncology. Lippincott, Philadelphia, pp 895–964 [Google Scholar]
- De Angelis P, Stokke T, Smedshammer L, Lothe RA, Lehne G, Chen Y, Clausen OPF (1995) P-glycoprotein is not expressed in a majority of colorectal carcinomas and is not regulated by mutantp53 in vivo. Br J Cancer 72:307–311 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Efferth T, Volm M (1992) Immunocytochemical detection of oncoproteins in animal and human tumour lines with acquired or inherent multidrug resistance. Cancer Detect Prev 16:237–243 [PubMed] [Google Scholar]
- Elrouby S, Thomas A, Costin D, Rosenberg CR, Potmesil M, Silber R, Newcomb EW (1993)p53 gene mutation in B-cell chronic lymphocytic leukemia is associated with drug resistance and is independent ofMDR1/MDR3 gene expression. Blood 82:3452–3459 [PubMed] [Google Scholar]
- Fojo AT, Ueda K, Slamon DJ, Poplack DG, Gottesman MM, Pastan I (1987) Expression of a multidrug-resistance gene in human tumours and tissues. Proc Natl Acad Sci USA 84:265–269 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Goldsmith ME, Gudas JM, Schneider E, Cowan KH (1995) Wildtypep53 stimulates expression from the human multidrug resistance promoter in ap53-negative cell line. J Biol Chem 270:1894–1898 [PubMed] [Google Scholar]
- Goldstein LJ, Galski H, Fojo A, Willingham M, Lai SL, Gazdar A, Pirker R, Green A, Crist W, Brodeur GM, Lieber M, Cossman J, Gottesman MM, Pastan I (1989) Expression of a multidrug resistance gene in human cancers. J Natl Cancer Inst 81:116–124 [DOI] [PubMed] [Google Scholar]
- Gottesman MM, Pastan I (1988) The multidrug transporter, a double-edged sword. Trends Biochem Sci 263:12163–12166 [PubMed] [Google Scholar]
- Kramer R, Weber RK, Morse B, Arceri R, Staniunas R, Steele G Jr, Summerhayes IC (1993) Constitutive expression of multidrug resistance in human colorectal tumours and cell lines. Br J Cancer 67:959–968 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Lai S, Goldstein LJ, Gottesman MM, Pastan I, Tsai CM, Johnson BE, Mulshine J, Ihde DC, Kayser K, Gazdar AF (1989)MDR1 gene expression in lung cancer. J Natl Cancer Inst 81:1144–1150 [DOI] [PubMed] [Google Scholar]
- Preudhomme C, Lepelley P, Vachee A, Soenen V, Quesnel B, Cosson A, Fenaux P (1993) Relationship betweenp53 gene mutations and multidrug resistance (mdr1) gene expression in myelodysplastic syndromes. Leukemia 7:1888–1890 [PubMed] [Google Scholar]
- Ragimov N, Krauskopf A, Navot N, Rotter V, Oren M, Aloni Y (1993) Wild-type but not mutantp53 can repress transcription initiation in vitro by interfering with the binding of basal transcription factors to the TATA motif. Oncogene 8:1183–1193 [PubMed] [Google Scholar]
- Reisman D, Elkind NB, Roy B, Beamon J, Rotter V (1993) c-myc trans-activates thep53 promoter through a required downstream CACGTG motif. Cell Growth Differ 4:57–65 [PubMed] [Google Scholar]
- Rochlitz CF, De-Kant E, Neubauer A, Heide I, Böhmer R, Oertel J, Huhn D, Herrmann R (1992a) PCR-determined expression of theMDR1 gene in chronic lymphocytic leukemia. Ann Hematol 65:241–246 [DOI] [PubMed] [Google Scholar]
- Rochlitz CF, Lobeck H, De Kant E, Mohr B, Reuter J, Peter S, Huhn D, Herrmann R (1992b) Multiple drug resistance gene expression in human renal cell cancer is associated with the histological subtype. Cancer 69:2993–2998 [DOI] [PubMed] [Google Scholar]
- Rochlitz CF, Heide I, De Kant E, Böhmer R, Peter FJ, Neuhaus P, Huhn D, Herrmann R (1993) Position specificity of Ki-ras oncogene mutations during the progression of colorectal carcinoma. Oncology 50:70–76 [DOI] [PubMed] [Google Scholar]
- Rochlitz CF, Heide I, Thiede C, Herrmann R, De Kant E (1995) Evidence for a mutual regulation ofp53 and c-myc expression in human colorectal cancer metastases. Ann Onco 6:981–986 [DOI] [PubMed] [Google Scholar]
- Schneider J, Rubio MP, Barbazan MJ, Rodriguez-Escudero FJ, Seizinger BR, Castresana JS (1994) P-glycoprotein, HER-2/neu, and mutantp53 expression in human gynecologic tumours [see comments]. J Natl Cancer Inst 86:850–855 [DOI] [PubMed] [Google Scholar]
- Strauss BE, Haas M (1995) The region 3′ to the major transcriptional start site of theMDR1 downstream promoter mediates activation by a subset of mutantp53 proteins. Biochem Biophys Res Commun 217:333–340 [DOI] [PubMed] [Google Scholar]
- Teeter LD, Eckersberg T, Tsai Y, Kuo MT (1991) Analysis of the Chinese hamster P-glycoprotein/multidrug resistance genePgp1 reveals that the AP-1 site is essential for full promoter activity. Cell Growth Differ 2:429–437 [PubMed] [Google Scholar]
- Thiebaut F, Tsuruo T, Hamada H, Gottesman MM, Pastan I, Willingham MC (1987) Cellular localization of the multidrug-resistance gene productP-glycoprotein in normal human tissues. Proc Natl Acad Sci USA 84:7735–7738 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Volm M (1993) P-glycoprotein associated expression of c-fos and c-jun products in human lung carcinomas. Anticancer Res 13:375–378 [PubMed] [Google Scholar]
- Weinstein RS, Jakate SM, Dominguez JM, Lebovitz MD, Koukoulis GK, Kuszak JR, Klusens LE, Grogan TM, Saclarides TJ, Roninson IB, Coon JS (1991) Relationship of the expression of the multidrug resistance gene product (P-glycoprotein) in human colon carcinoma to local tumour aggressiveness and lymph node metastasis. Cancer Res 51:2720–2726 [PubMed] [Google Scholar]
- Zastawny RL, Salvino R, Chen J, Benchimol S, Ling V (1993) The core promoter region of theP-glycoprotein gene is sufficient to confer differential responsiveness to wild-type and mutantp53. Oncogene 8:1529–1535 [PubMed] [Google Scholar]
