Abstract
Ovarian cancer is a leading cause of cancer death in women in the United States. While the majority of ovarian cancers are serous, some rarer subtypes (i.e. clear cell) are often associated with endometriosis, a benign gynecological disease. Iron is rich in the cyst fluid of endometriosis-associated ovarian cancers and induces persistent oxidative stress. The role of iron, an essential nutrient involved in multiple cellular functions, in normal ovarian cell survival and ovarian cancer remains unclear. Iron, presented as ferric ammonium citrate (FAC), dramatically inhibits cell survival in ovarian cancer cell types associated with Ras mutations, while it is without effect in immortalized normal ovarian surface epithelial (T80) and endometriotic epithelial cells (lacking Ras mutations). Interestingly, FAC induced changes in cytoplasmic vacuolation concurrently with increases in LC3-II levels (an autophagy marker); these changes occurred in an ATG5/ATG7-dependent, beclin-1/hVps34-independent, and Ras-independent manner. Knockdown of autophagy mediators in HEY ovarian cancer cells reversed FAC-induced LC3-II levels, but there was little effect on reversing the cell death response. Intriguingly, transmission electron microscopy of FAC-treated T80 cells demonstrated abundant lysosomes (confirmed using Lysotracker) rich in iron particles, which occurred in a Ras-independent manner. Although the mitogen-activated protein kinase (MAPK) inhibitor, U0126, reversed FAC-induced LC3-II/autophagic punctae and lysosomes in a Ras-independent manner, it was remarkable that U0126 reversed cell death in malignant ovarian cells associated with Ras mutations. Moreover, FAC increased heme oxygenase-1 expression in H-Ras-overexpressing T80 cells, which was associated with increased cell death when overexpressed in T80 cells. Disruption of intracellular iron levels, via chelation of intracellular iron (deferoxamine), was also detrimental to malignant ovarian cell survival; thus, homeostatic intracellular iron levels are essential for cell survival. Collectively, our results implicate iron in modulating cell death in a Ras- and MAPK-dependent manner in ovarian cancer cells.
Highlights
Several ovarian cancer subtypes exist that elicit differential responses to chemotherapy
Reports indicate that cancer cell lines respond to iron with increased proliferative indices, we demonstrate that iron is detrimental to the survival of ovarian cancer cells associated with Ras mutations (Figure 8)
The frequency of Ras mutations in ovarian cancers is variable owing to the heterogeneity of this disease, we propose that cellular sensitivity towards iron may be a novel targeting strategy
Summary
Several ovarian cancer subtypes exist that elicit differential responses to chemotherapy. Reactive oxygen species (ROS) can be generated via hypoxia, correlated with elevated LC3A (a marker of autophagy) expression in CCC associated with hypoxic regions and poor patient outcome.[7] Autophagy is a selfeating process where damaged and oxidized cellular material are sequestered in autophagosomes and degraded within lysosomes.[8] Autophagy elicits tumor suppressive effects in normal cells, while under conditions of oxidative stress, autophagy sustains survival of cancer cells It is presently unknown whether oxidative stress induced by iron alters autophagy to modulate cell survival in normal and malignant ovarian cells. We demonstrate that iron modulates cell death in ovarian cancer cell types in a Ras- and MAPK-dependent manner
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