Increased Expression of Annexin A3 Is a Mechanism of Platinum Resistance in Ovarian Cancer

Abstract

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 phospholipidbinding 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. Cancer Res; 70(4); 1616-24. ©2010 AACR.

Regulatory Mechanisms of Annexin-Induced Chemotherapy Resistance in Cisplatin Resistant Lung Adenocarcinoma

“…Meanwhile, recent research results indicated that A3 expression in the tissues of patients with cisplatin-resistant prostate cancer and ovarian cancer has increased significantly. In addition, the cycles of patients without tumors in the A3 high expression group are clearly shortened (Gillette et al, 2004;Huang et al, 2008) Related studies also prove that A3 produces drug resistance by reducing the platinum content, the platinum-DNA combining quantity within cells, and the p53 level in ovarian cancer cells (Yan et al, 2010). The tumorigenesis of cells with high A3 expression is significantly increased after cisplatin treatment, as demonstrated through an animal experiment.…”

“…The tumorigenesis of cells with high A3 expression is significantly increased after cisplatin treatment, as demonstrated through an animal experiment. In addition, the resistance of cells with high A3 expression is clearly enhanced against platinum-based medicines; however, it does not induce cross-resistance with TAX and EPI (Yan et al, 2010).…”

Metformin, at Concentrations Corresponding to the Treatment of Diabetes, Potentiates the Cytotoxic Effects of Carboplatin in Cultures of Ovarian Cancer Cells

“…As the first line of treatment for advanced ovarian cancer is commonly carboplatin in combination with paclitaxel, we specifically chose to use the cell lines A2780 and SKOV3, as they demonstrate sensitivity to paclitaxel, while showing resistance to low micromolar concentrations of carboplatin, which are deemed representative of the concentration reaching the tumor cell in the patient. 22,23 Figure 1 demonstrates a concentration response of metformin in the range of 1 mmol/L to 50 mmol/L. As shown, micromolar concentrations of metformin do not statistically reduce the viability of either the A2780 or the SKOV3 ovarian cancer cell lines; however, at 48 hours, millimolar concentrations bring about cell death at each of the 3 millimolar concentrations tested.…”

S100 and annexin proteins identify cell membrane damage as the Achilles heel of metastatic cancer cells

“…78 Further, changes in annexin A3 and A4 expression has been associated with chemo resistance in ovarian cancer cells. 79,80 These findings make a case for a potential therapeutic approach against tumor metastasis that could involve targeting PMR by regulating expression of specific annexins. However, in view of the sequence homology of the annexins and use of multiple annexins in PMR, suggests the likelihood of functional redundancy between the family members.…”