Activation of DRD5 (dopamine receptor D5) inhibits tumor growth by autophagic cell death
| Autor: | Xun Zhang, Han Bing Shang, Ya Jun Xue, Hao Tang, Lin Cai, Weidong Le, Zhe Bao Wu, Yu Hang Guo, Wei Guo Zhao, Shao Jian Lin, Mei Qing Lou, Ze Rui Wu, Wenxiu Zhao, Zhi Gen Leng |
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| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
medicine.medical_specialty Programmed cell death Translational Research Paper Cabergoline Mice Nude Biology Dopamine agonist 03 medical and health sciences Internal medicine Cell Line Tumor medicine Autophagy Animals Humans Pituitary Neoplasms Receptors Dopamine D5 Ergolines Molecular Biology PI3K/AKT/mTOR pathway Prolactinoma Cell Proliferation Superoxide Dismutase TOR Serine-Threonine Kinases Pituitary tumors Autophagosomes Cancer Cell Biology medicine.disease Rats 030104 developmental biology Endocrinology Cancer research 2 3 4 5-Tetrahydro-7 8-dihydroxy-1-phenyl-1H-3-benzazepine Reactive Oxygen Species medicine.drug |
| Popis: | Dopamine agonists such as bromocriptine and cabergoline have been successfully used in the treatment of pituitary prolactinomas and other neuroendocrine tumors. However, their therapeutic mechanisms are not fully understood. In this study we demonstrated that DRD5 (dopamine receptor D5) agonists were potent inhibitors of pituitary tumor growth. We further found that DRD5 activation increased production of reactive oxygen species (ROS), inhibited the MTOR pathway, induced macroautophagy/autophagy, and led to autophagic cell death (ACD) in vitro and in vivo. In addition, DRD5 protein was highly expressed in the majority of human pituitary adenomas, and treatment of different human pituitary tumor cell cultures with the DRD5 agonist SKF83959 resulted in growth suppression, and the efficacy was correlated with the expression levels of DRD5 in the tumors. Furthermore, we found that DRD5 was expressed in other human cancer cells such as glioblastomas, colon cancer, and gastric cancer. DRD5 activation in these cell lines suppressed their growth, inhibited MTOR activity, and induced autophagy. Finally, in vivo SKF83959 also inhibited human gastric cancer cell growth in nude mice. Our studies revealed novel mechanisms for the tumor suppressive effects of DRD5 agonists, and suggested a potential use of DRD5 agonists as a novel therapeutic approach in the treatment of different human tumors and cancers. |
| Databáze: | OpenAIRE |
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