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, 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
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.
Keywords: MTOR; autophagic cell death; cabergoline; dopamine agonist; dopamine receptor D5; prolactinoma; reactive oxygen species.
Figures
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Figure 5.
Activation of DRD5 induces autophagy…
Figure 5.
Activation of DRD5 induces autophagy and blocks autophagic flux in pituitary tumor cells.…
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Critical role of autophagy in…
Figure 6.
Critical role of autophagy in DRD5-mediated suppression of pituitary tumor cell growth. (A)…
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Growth suppression by DRD5 activation…
Figure 7.
Growth suppression by DRD5 activation in human pituitary tumor primary cultures. (A) Western…
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Growth suppression and autophagy activation…
Figure 8.
Growth suppression and autophagy activation by DRD5 activation in human cancer cells. (A)…
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- 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine / analogs & derivatives
- 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine / pharmacology
- Animals
- Autophagosomes / drug effects
- Autophagosomes / metabolism
- Autophagosomes / ultrastructure
- Autophagy* / drug effects
- Cabergoline
- Cell Line, Tumor
- Cell Proliferation / drug effects
- Ergolines / pharmacology
- Ergolines / therapeutic use
- Humans
- Mice, Nude
- Pituitary Neoplasms / drug therapy
- Pituitary Neoplasms / metabolism*
- Pituitary Neoplasms / pathology*
- Pituitary Neoplasms / ultrastructure
- Rats
- Reactive Oxygen Species / metabolism
- Receptors, Dopamine D5 / genetics
- Receptors, Dopamine D5 / metabolism*
- Superoxide Dismutase / metabolism
- TOR Serine-Threonine Kinases / metabolism
- DRD5 protein, human
- Ergolines
- Reactive Oxygen Species
- Receptors, Dopamine D5
- 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine
- SK&F 83959
- Superoxide Dismutase
- TOR Serine-Threonine Kinases
- Cabergoline
- Full Text Sources
- Other Literature Sources
- Medical
- Miscellaneous
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Source: PubMed