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

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.

Treatment of Pituitary and Other Tumours with Cabergoline: New Mechanisms and Potential Broader Applications

“…Furthermore, the mechanism for mTOR activation and induction of ACD was not restricted in pituitary tumour cells. Similar results were obtained with other human cancer cells, such as colon cancer, gastric cancer, and glioblastoma cells, due to the high expression of DRD5, suggesting a potential broad therapeutic application of CAB in different human tumours [5].…”

“…In addition, D2S was observed to activate phospholipase D, which may be linked to its potent antiproliferative effect [23]. Subsequent studies have revealed multiple mechanisms for the anti-proliferative function of dopamine agonists (DAs) [5,24].…”

“…Thus, CAB initiated autophagy but disrupted autophagic flux, resulting in ACD [24]. Using receptor-specific agonists and antagonists, combined with RNAi technology, Leng et al [5] identified that DRD5 was responsible for CAB-mediated ACD via mTOR activation. Furthermore, the mechanism for mTOR activation and induction of ACD was not restricted in pituitary tumour cells.…”

“…Compared to bromocriptine (BRC), CAB is more potent in binding to the D2 dopamine receptor (DRD2), which causes AC inhibition, decreases cAMP and induces apoptosis. Meanwhile, CAB induces autophagic cell death (ACD) by activating DRD5 [2][3][4][5]. CAB is better tolerated than BRC in the majority of patients, with fewer side effects and more convenient dosing schedules.…”

FOXO1, a Potential Therapeutic Target, Regulates Autophagic Flux, Oxidative Stress, Mitochondrial Dysfunction, and Apoptosis in Human Cholangiocarcinoma QBC939 Cells

“…It has been recognized that control of autophagy progression in cancer cells is an effective strategy to halt tumor growth [24, 25], as the molecular analyses of human cancers have revealed that autophagy regulators are frequently deregulated in most of the common malignancies [26, 27]. For this reason, autophagy inhibition has been regarded as a promising anticancer strategy to inhibit the multiple cellular processes.…”