Increased expression of annexin A3 is a mechanism of platinum resistance in ovarian cancer.
Resistance to platinum drugs has emerged as a major obstacle in the treatment of ovarian cancers. Through proteomic analysis, we have found that the expression of annexin A3, a member of the Ca(2+) and phospholipid-binding annexin family, is significantly increased in platinum-resistant ovarian cell lines. Anti-annexin A3 immunostaining indicated that cancers from platinum-resistant patients also possess higher levels of annexin A3 than those from platinum-sensitive patients. Although expression of annexin A3 made susceptible ovarian cancer cells more resistant to platinum, expression of antisense annexin A3 downregulated its expression and rendered the resistant cells more sensitive to platinum. In athymic mice, the growth of tumors from inoculated SKOV3 cells was inhibited by the administration of platinum, whereas tumors from annexin A3-expressing SKOV3/Ann were resistant to platinum treatment. Interestingly, the intracellular platinum concentration and platinum-DNA binding are significantly lower in annexin A3-overexpressing cells than those in parental cells. The lower cisplatin concentration was also accompanied by reduced induction of p53, which could be restored by downregulation of annexin A3. These results indicate that increased expression of annexin A3 is a mechanism of platinum resistance in ovarian cancer. It seems to act by preventing uptake or accumulation of platinum in cells. Therefore, it is conceivable that annexin A3 could be a target for therapeutic intervention and may also serve as a biomarker for drug resistance in ovarian cancer patients.
Yan
Xuedong
X
Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China.
Yin
Jie
J
Yao
Huiyu
H
Mao
Ning
N
Yang
Yili
Y
Pan
Lingya
L
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D017318:Annexin A3 / Q000235:genetics*; D000970:Antineoplastic Agents / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000235:genetics / Q000502:physiology; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D009375:Neoplasms, Glandular and Epithelial / Q000188:drug therapy* / Q000235:genetics*; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D017671:Platinum Compounds / Q000627:therapeutic use*; D014407:Tumor Cells, Cultured; D015854:Up-Regulation / Q000502:physiology; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D017671:Platinum Compounds; D017318:Annexin A3