DEPTOR inhibits cell proliferation and confers sensitivity to dopamine agonist in pituitary adenoma

  • Cancer Lett. 2019 Sep 10;459:135-144. doi: 10.1016/j.canlet.2019.05.043.
Hong Yao  1 ,  Hao Tang  1 ,  Yong Zhang  1 ,  Qiu Fen Zhang  2 ,  Xin Yi Liu  2 ,  Yan Ting Liu  3 ,  Wei Ting Gu  1 ,  Yong Zhi Zheng  4 ,  Han Bing Shang  1 ,  Yu Wang  5 ,  Jin Yan Huang  6 ,  Yong Xu Wei  1 ,  Xun Zhang  7 ,  Jian Zhang  8 ,  Zhe Bao Wu  9
Affiliations
  • 1. Department of Neurosurgery, Center of Pituitary Tumor, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 2. Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Medicinal Bioinformatics Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 3. Department of Neurosurgery, Center of Pituitary Tumor, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Department of Neurosurgery, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
  • 4. Department of Neurosurgery, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
  • 5. Department of Neurosurgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 6. State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 7. Neuroendocrine Research Laboratory, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
  • 8. Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Medicinal Bioinformatics Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Electronic address: [email protected].
  • 9. Department of Neurosurgery, Center of Pituitary Tumor, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Department of Neurosurgery, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China. Electronic address: [email protected].
PMID: 31176743 DOI: 10.1016/j.canlet.2019.05.043
Abstract

DEP domain-containing mechanistic target of rapamycin (mTOR)-interacting protein (DEPTOR) is an important modulator of mTOR, a highly conserved kinase whose hyperactivation is critically involved in a variety of human tumors. The role of DEPTOR playing in pituitary adenoma (PA) is largely unknown. Here, we reported that DEPTOR was downregulated in PA tissues, especially dopamine-resistant prolactinomas. Consistently, overexpression of DEPTOR inhibited pituitary tumor GH3 and MMQ cells proliferation in vitro and in vivo, and sensitized GH3 and MMQ cells to cabergoline (CAB), a dopamine agonist (DA). Conversely, knockdown of DEPTOR promoted GH3 and MMQ cells proliferation, and conferred cells resistance to CAB. Mechanistically, DEPTOR inhibited both mTOR Complex 1 (mTORC1) and 2 (mTORC2) activities in PA cells. In addition, DEPTOR expression level was increased to suppress mTOR kinase activity via decreasing E3 ubiquitin Ligase, βTrCP1, in response to CAB. Furthermore, DEPTOR enhanced autophagy-dependent cell death to confer cells sensitivity to CAB. Taken together, our results suggest that DEPTOR may be a potential target for the treatment of PAs.

Keywords
Autophagy; Cabergoline; Prolactinoma; mTOR.
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