The prolactin‐release inhibitor paeoniflorin suppresses proliferation and induces apoptosis in prolactinoma cells via the mitochondria‐dependent pathway

Abstract

Prolactinomas are the most prevalent functional pituitary adenomas that cause chronic pathological hyperprolactinemia. Prolactin is known to promote cell growth and inhibit apoptosis in cells. Paeoniflorin is the principal component of radix Paeoniae alba (the main ingredient in some traditional herbal formulas clinically used for hyperprolactinemia-associated disorders). Recent findings from intensive studies have suggested that paeoniflorin regulates cell proliferation and apoptosis in many cell lines. However, the effects of paeoniflorin in pituitary tumor cells remain unknown. Here the results by the Cell Counting Kit-8 and colony formation assays showed that paeoniflorin concentration-dependently decreased cell viability in both MMQ and GH3 cells and colony formation in GH3 cells, suggesting inhibition of cell proliferation by paeoniflorin. By flow cytometry, paeoniflorin was found to increase apoptotic rate in MMQ cells. Mechanistically, Western blot results revealed that paeoniflorin enhanced protein expression of cleave caspase-9 and -3, and Bax, whereas it suppressed Bcl-2 protein expression in MMQ cells. Furthermore, paeoniflorin upregulated phosphorylated p53 protein expression, but it decreased prolactin concentration and prolactin protein expression in both MMQ and GH3 cells. Thus, the present results demonstrate that paeoniflorin inhibits cell proliferation and induces the mitochondrial pathway-mediated apoptosis in prolactinoma cells. These antitumor property is associated with inhibition of prolactin secretion. Our findings may provide new insight into the mechanisms underlying improving prolactinoma-associated disorders of paeoniflorin-enriched herbs and formulas.

The Anticancer Effects of Paeoniflorin and Its Underlying Mechanisms

“…31 It is believed that the upregulation of pro-apoptosis factor Bax and the downregulation of anti-apoptosis factor Bcl-2 lead to cell apoptosis. As shown in some research, PF increases the Bax-to-Bcl-2 ratio in HepG2, SMMC-7721, 59 HeLa, 27 RT4, 31 MMQ, 60 HOS, and Saos-2 cells. 25 Mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathway.…”

“…33 PF was also reported to upregulate both cleave caspase-3 and -9 in prolactinoma MMQ cells in a concentration-dependent manner. 60 Activation of caspase-3 and -9 was also detected in PF-treated BXPC-3, 29 SKO-007, 35 and HT29 cells. 57 Yang et al found that PF increased the activities of caspase-3, caspase-8, and caspase-9, thus inducing apoptosis in bladder carcinoma RT4 cells.…”

“…22 A novel study revealed that by inhibiting prolactin, PF induces prolactinoma cell apoptosis through the mitochondria-dependent pathway, which is related to phosphorylated P53 upregulation. 60 Moreover, PF-induced apoptosis of A549 cells is due to activation of the Fas/Fas ligand apoptotic system, reflected in the increased expression of Fas/apoptosis-1 and its 2 ligands. 24 PF is reported to have a cytotoxic effect on HL-60 and other leukemia cell lines through the inhibition of Fos-Jun-DNA complex formation.…”

Oxidative stress in pituitary neuroendocrine tumors: Affecting the tumor microenvironment and becoming a new target for pituitary neuroendocrine tumor therapy

“…Melatonin is able to selectively block the production of VEGF and ROS and even reverse angiogenesis, which can result in reduced ROS and a lack of tumor nutrition in the TME 193 . Paeoniflorin increased the expression of cleaved caspase‐9, caspase‐3, and Bax and inhibited the expression of Bcl‐2 in MMQ cells and GH3 cells, thereby inducing mitochondria‐mediated apoptosis, which ultimately manifested as a decrease in cell viability and inhibited proliferation 194,195 …”

Architects of Pituitary Tumour Growth

“…Indeed, elevated mitophagy and mitochondrial dysfunction may favour resistance to chemotherapy in the pituitary GH3 cell line ( 131 ). Conversely, activation of mitochondria-mediated apoptosis has been proposed, which might favour novel therapy drugs ( 132 – 134 ). Although this evidence validates the significant roles of mitochondrial functions and adaptability in pituitary tumorigenesis, their molecular mechanisms still need to be clarified.…”