Autophagy protects ovarian cancer-associated fibroblasts against oxidative stress

• Published in: Cell cycle (Georgetown, Tex.) Tex.), 2016-05, Vol.15 (10), p.1376-1385
• Main Authors: Wang, Qian, Xue, Liang, Zhang, Xiaoyu, Bu, Shixia, Zhu, Xueliang, Lai, Dongmei
• Format: Article
• Language: English
• Subjects: Acetylcysteine - pharmacology; Actins - metabolism; Autophagy - drug effects; Autophagy-Related Protein 5 - antagonists & inhibitors; Autophagy-Related Protein 5 - genetics; Autophagy-Related Protein 5 - metabolism; Cancer-Associated Fibroblasts - cytology; Cancer-Associated Fibroblasts - drug effects; Cancer-Associated Fibroblasts - metabolism; Cell Proliferation - drug effects; Cell Survival - drug effects; Cells, Cultured; Cyclin-Dependent Kinase Inhibitor p21 - metabolism; Female; Fibroblasts - cytology; Fibroblasts - drug effects; Fibroblasts - metabolism; Humans; Hydrogen Peroxide - toxicity; Isoenzymes - metabolism; L-Lactate Dehydrogenase - metabolism; Monocarboxylic Acid Transporters - metabolism; Muscle Proteins - metabolism; Ovarian Neoplasms - metabolism; Ovarian Neoplasms - pathology; Oxidative Stress - drug effects; Reactive Oxygen Species - metabolism; S Phase Cell Cycle Checkpoints - drug effects; Superoxide Dismutase - metabolism
• ISSN: 1538-4101; 1551-4005
• DOI: 10.1080/15384101.2016.1170269

RNA-Seq and gene set enrichment anylysis revealed that ovarian cancer associated fibroblasts (CAFs) are mitotically active compared with normal fibroblasts (NFs). Cellular senescence is observed in CAFs treated with H2O2 as shown by elevated SA-β-gal activity and p21 (WAF1/Cip1) protein levels. Reactive oxygen species (ROS) production and p21 (WAF1/Cip1) elevation may account for H2O2-induced CAFs cell cycle arrest in S phase. Blockage of autophagy can increase ROS production in CAFs, leading to cell cycle arrest in S phase, cell proliferation inhibition and enhanced sensitivity to H2O2-induced cell death. ROS scavenger NAC can reduce ROS production and thus restore cell viability. Lactate dehydrogenase A (LDHA), monocarboxylic acid transporter 4 (MCT4) and superoxide dismutase 2 (SOD2) were up-regulated in CAFs compared with NFs. There was relatively high lactate content in CAFs than in NFs. Blockage of autophagy decreased LDHA, MCT4 and SOD2 protein levels in CAFs that might enhance ROS production. Blockage of autophagy can sensitize CAFs to chemotherapeutic drug cisplatin, implicating that autophagy might possess clinical utility as an attractive target for ovarian cancer treatment in the future.