Annexin-I expression modulates drug resistance in tumor cells

• Published in: Biochemical and biophysical research communications Vol. 314; no. 2; pp. 565 - 570
• Main Authors: Wang, Ying, Serfass, Lucile, Roy, Marie-Odile, Wong, Judy, Bonneau, Anne-Marie, Georges, Elias
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 06.02.2004
• Subjects: Adriamycin; Annexin A1 - genetics; Annexin A1 - physiology; Annexin-I; Annexins - metabolism; Antibiotics, Antineoplastic - pharmacology; Antineoplastic Agents - pharmacology; Antineoplastic Agents, Alkylating - pharmacology; Antineoplastic Agents, Phytogenic - pharmacology; ATP Binding Cassette Transporter, Subfamily B, Member 1 - metabolism; ATP Binding Cassette Transporter, Subfamily G, Member 2; ATP-Binding Cassette Transporters - metabolism; Blotting, Northern; Cell Line, Tumor; Cloning, Molecular; DNA, Complementary - metabolism; Dose-Response Relationship, Drug; Doxorubicin - pharmacology; Drug Resistance, Neoplasm; Etoposide; Etoposide - pharmacology; Gene Library; HeLa Cells; Humans; MCF-7; MDA-MB-231; Melphalan; Melphalan - pharmacology; Multidrug resistance; Multidrug Resistance-Associated Proteins - metabolism; Neoplasm Proteins - metabolism; Open Reading Frames; Protein Biosynthesis; RNA - metabolism; SKOV-3; Transcription, Genetic; Transfection; Annexin-I; Multidrug resistance; MCF-7; Adriamycin; Melphalan; Etoposide; SKOV-3; MDA-MB-231
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2003.12.117

The use of anti-cancer chemotherapy often leads to the rise of multidrug-resistant (MDR) tumors. We have previously reported the overexpression of a 40 kDa protein (P-40) in several MDR tumor cell lines. In this report we describe the cloning of a 1.4 kb cDNA with an open reading frame of 344 amino acids that encodes the P-40 protein. Analysis of the P-40 amino acid sequence showed it is identical to the human annexin I (Anx-I) protein. The identity of the isolated P-40 cDNA as Anx-I was confirmed by the specific binding of IPM96 mAb to a 40 kDa protein following the in vitro expression of P-40 full-length cDNA. Northern blot analysis of total RNA from drug-sensitive and -resistant cells revealed an increase in P-40 (or Anx-I) mRNA in drug-resistant cells relative to drug-sensitive cells. Transfection of Anx-I cDNA into drug-sensitive MCF-7 cells was carried out without further drug selection and showed 2- to 5-fold increase in resistance of transfected cells to adriamycin, melphalan, and etoposide. Conversely, transfection of reverse Anx-I cDNA into SKOV-3 cells decreased the expression of Anx-I without affecting the expression of other members of the annexin family and showed a 3- to 8-fold increase in sensitivity to these drugs. Of interest was the correlation between the presence of Anx-I and MDR in MDA-MB-231 cells when compared to MCF-7 cells. MDA-MB-231 cells show 3- to 20-fold increase in resistance to adriamycin, melphalan, and etoposide in the absence of detectable levels of P-glycoprotein (P-gp1), the multidrug resistance protein (MRP1) or the breast cancer resistance protein (BCRP). Taken together, these results provide the first direct evidence for the role of Anx-I in MDR of tumor cells.