Activation of DRD5 (dopamine receptor D5) inhibits tumor growth by autophagic cell death

Zhi Gen Leng, Shao Jian Lin, Ze Rui Wu, Yu Hang Guo, Lin Cai, Han Bing Shang, Hao Tang, Ya Jun Xue, Mei Qing Lou, Wenxiu Zhao, Wei Dong Le, Wei Guo Zhao, Xun Zhang, Zhe Bao Wu

Research output: Contribution to journalArticle

38 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1404-1419
Number of pages16
JournalAutophagy
Volume13
Issue number8
DOIs
StatePublished - Aug 3 2017

Keywords

  • MTOR
  • autophagic cell death
  • cabergoline
  • dopamine agonist
  • dopamine receptor D5
  • prolactinoma
  • reactive oxygen species

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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