Abstract
Epithelial ovarian cancer has the highest mortality rate of all gynecologic cancers. Cancer stem cells are considered to be the initiating cells of tumors. It is known that spheroid culture promotes ovarian cancer cells to acquire stem cell characteristics and to become stem cell-like. But the mechanisms remain largely unclear. Our data show that autophagy is sustainably activated in ovarian cancer spheroid cells. Inhibition of autophagy by knockdown of ATG5 abolishes the self-renewal ability of ovarian cancer spheroid cells. Knockdown of ATG5 prevents ovarian cancer spheroid cells to enter quiescent state. Autophagy is critical for quiescent ovarian cancer spheroid cells to reenter the cell cycle because rapamycin can promote quiescent ovarian cancer spheroid cells to form colonies on soft agar and knockdown of ATG5 can arrest ovarian cancer cells in G0/G1. Autophagy and NRF2 form a positive feedback regulation loop to regulate reactive oxygen species (ROS) levels in ovarian cancer spheroid cells. The optimal ROS level, neither too high nor too low, facilitates the self-renewal marker, NOTCH1, to reach to the highest level. Bafilomycin A1 can impair the self-renewal of ovarian cancer spheroid cells by disturbing ROS levels.
Highlights
Epithelial ovarian cancer has the highest mortality rate of all gynecologic cancers
Epithelial cells and fibroblasts were the two major populations derived from primary ovarian cancer tissue, which can be differentiated by keratin 18 stain
The keratin 18-positive epithelial cells can form spheroid cells (Figures S2(a) and S2(b)). cDNA array data showed that several autophagy pathway essential genes, including MAP1LC3B, ATG16L1, RB1CC1, and ULK1, were upregulated in SKOV3 spheroid cells compared with adherent cells (Figure S3(a)), suggesting that autophagy might be activated in SKOV3 spheroid cells
Summary
Epithelial ovarian cancer has the highest mortality rate of all gynecologic cancers. Ovarian cancer stem-like and initiating cells can be isolated in ovarian cancer cell lines, primary ovarian tumors, and the ascites of ovarian cancer patients. These cells express stem cell markers, resist to chemotherapeutic agents, and establish tumors in animal models [4,5,6]. It is widely accepted that spheroid culture promotes ovarian cancer cells to acquire stem cell characteristics and become stem cell-like [7, 8]. The regulatory mechanisms of ovarian cancer spheroid cells maintaining their stem cell-like properties are largely unknown
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