title: Inhibition of SKP2 Sensitizes Bromocriptine-Induced Apoptosis in Human Prolactinoma Cells.
abstract: OBJECTIVE
  Prolactinoma (prolactin-secreting pituitary adenoma) is one of the most common estrogen-related functional pituitary tumors. As an agonist of the dopamine D2 receptor, bromocriptine is used widely to inhibit prolactinoma progression. On the other hand, it is not always effective in clinical application. Although a dopamine D2 receptor deficiency contributes to the impaired efficiency of bromocriptine therapy to some extent, it is unknown whether there some other underlying mechanisms leading to bromocriptine resistance in prolactinoma treatment. That is the main point addressed in this project.
  
  
  METHODS
  Human prolactinoma samples were used to analyze the S-phase kinase associated protein 2 (SKP2) expression level. Nutlin-3/adriamycin/cisplatin-treated GH3 and MMQ cells were used to analyze apoptosis in SKP2 overexpression or knockdown cells. SKP2 expression and the interaction partners of SKP2 were also detected after a bromocriptine treatment in 293T. Apoptosis was analyzed in C25 and bromocriptine-treated GH3 cells.
  
  
  RESULTS
  Compared to normal pituitary samples, most prolactinoma samples exhibit higher levels of SKP2 expression, which could inhibit apoptosis in a p53-dependent manner. In addition, the bromocriptine treatment prolonged the half-life of SKP2 and resulted in SKP2 overexpression to a greater extent, which in turn compromised its pro-apoptotic effect. As a result, the bromocriptine treatment combined with C25 (a SKP2 inhibitor) led to the maximal apoptosis of human prolactinoma cells.
  
  
  CONCLUSIONS
  These findings indicated that SKP2 inhibition sensitized the prolactinoma cells to bromocriptine and helped promote apoptosis. Moreover, a combined treatment of bromocriptine and C25 may contribute to the maximal apoptosis of human prolactinoma cells.
authors.affiliation: Department of Neurosurgery, Shanghai Institute of Neurosurgery, Changzheng Hospital, Second Military Medical University, Shanghai, China.
authors.forename: Jinxiang
authors.initials: J
authors.lastname: Huang
authors.affiliation: Department of Neurosurgery, The 411th Hospital of PLA, Shanghai, China.
authors.forename: Fenglin
authors.initials: F
authors.lastname: Zhang
authors.affiliation: Department of Neurosurgery, Shanghai Institute of Neurosurgery, Changzheng Hospital, Second Military Medical University, Shanghai, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Jiang
authors.affiliation: Department of Neurosurgery, Shanghai Institute of Neurosurgery, Changzheng Hospital, Second Military Medical University, Shanghai, China.
authors.forename: Guohan
authors.initials: G
authors.lastname: Hu
authors.affiliation: Department of Neurosurgery, Shanghai Institute of Neurosurgery, Changzheng Hospital, Second Military Medical University, Shanghai, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Sun
authors.affiliation: Department of Neurosurgery, Shanghai Institute of Neurosurgery, Changzheng Hospital, Second Military Medical University, Shanghai, China.
authors.forename: Chenran
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Department of Neurosurgery, Shanghai Institute of Neurosurgery, Changzheng Hospital, Second Military Medical University, Shanghai, China.
authors.forename: Xuehua
authors.initials: X
authors.lastname: Ding
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics*; D001971:Bromocriptine / Q000494:pharmacology*; D045744:Cell Line, Tumor; D018491:Dopamine Agonists / Q000494:pharmacology*; D005260:Female; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D006801:Humans; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D010911:Pituitary Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism; D011388:Prolactin / Q000378:metabolism; D015175:Prolactinoma / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism; D059748:Proteolysis; D044786:S-Phase Kinase-Associated Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D047368:Tumor Burden; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D054875:Ubiquitination
chemical_list: D018491:Dopamine Agonists; D044786:S-Phase Kinase-Associated Proteins; D016159:Tumor Suppressor Protein p53; D001971:Bromocriptine; D011388:Prolactin
keywords: Apoptosis; Bromocriptine; C25; Prolactinoma; SKP2