2. Academic Validation
  3. DEPTOR inhibits cell proliferation and confers sensitivity to dopamine agonist in pituitary adenoma

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

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: jian.zhang@sjtu.edu.cn.
  • 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: zhebaowu@aliyun.com.
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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