Table 1.

Drugs or molecules involved in MAPK signaling pathway in PAs.

Drugs or molecules involved in MAPK signaling pathway			Tumor subtype	Molecular mechanism	Biological effect	Research models	References
Therapeutic drugs	Somatostatin analogs (SSTs)	SOM230 (FDA approved)	GH-secreting PAs	SOM230 combines with somatostatin receptor subtype 2 (SSTR2) and inhibits ERK pathway	Inhibits GH release and proliferation of tumor cells	Primary GH-secreting adenoma cells, and rat pituitary cell line (GH3)	(13–15)
			PRL-secreting PAs	SOM230 combines with SSTR5 and inhibits ERK pathway	Inhibits PRL release and proliferation of tumor cells	Primary PRL-secreting adenoma cells, and rat pituitary cell line (GH3)	(13–15)
			Corticotropin-secreting PAs	SOM230 binds to SSTR5 not SSTR2 to inhibit ERK pathway	Suppresses CRH-induced ACTH release and decreases urinary free cortisol (UFC), and serum cortisol	AtT20/D16V mouse tumor cells, and pituitary dependent Cushing's disease patients	(16–18)
			Gonadotroph PAs	Suppresses the phosphorylation of ERK	Reduces GnRH-induced LH secretion	Mouse gonadotroph LβT2 cells	(19)
		Octreotide (OCT) (FDA approved)	GH-secreting PAs	OCT combines with SSTR2 and inhibits ERK pathway	Inhibits GH-release and proliferation of tumor cells	Primary GH-secreting adenoma cells, and rat pituitary cell line (GH3)	(13–15)
			Gonadotroph PAs	Suppresses the phosphorylation of ERK	Reduces GnRH-induced LH secretion	Mouse gonadotroph LβT2 cells	(19)
	Dopamine and Dopamine agonists	Dopamine	PRL-secreting PAs	Suppresses the phosphorylation of ERK1/2	Reduces PRL secretion	PRL-secreting cells (GH4ZR7), and primary pituitary cells	(20)
		Bromocriptine (BRC) (FDA approved)	PRL secreting pituitary adenoma	Activates p38 MAPK	Increases GH3 cell apoptosis	Rat pituitary cell line (GH3)	(21)
		Cabergoline (CAB) (FDA approved)	PRL secreting pituitary adenoma	Activates p38 MAPK	Increases GH3 cell apoptosis	PRL-D2S cells	(22)
	TGFβ		Lactosomatotroph PAs	Cross-talks with ERK pathway	Decreases the cell proliferation	Rat lactosomatotroph pituitary adenoma cells (GH3B6)	(23)
	18beta-glycyrrhetinic acid (GA)		GH-secreting PAs	Activates mitochondria-mediated ROS, JNK and P38 pathways	G0/G1 phase arrest and increases apoptosis rate	Rat pituitary adenoma-derived MMQ and GH3 cells	(24)
			PRL-secreting PAs
	The dopamine–somatostatin chimeric compound	BIM-23A760	NFPAs	Activates ERK1/2 and p38 pathways	Inhibits cell proliferation and induces apoptosis	Primary NFPA cells	(25)
	Ursolic Acid (UA)		ACTH-secreting PAs	Upregulates JNK phosphorylation and increases the degradation of Bcl-2	Induces apoptosis of AtT20 cells and decreases ACTH secretion	AtT20 pituitary corticotroph cell line	(26)
	Fulvestrant		GH-secreting PAs	Activates PTEN/MAPK signaling pathways	Increases apoptotic cell death	Rat pituitary cell line (GH3)	(27)
			PRL-secreting PAs
Potential targets	Raf kinase inhibitory protein (RKIP)		Somatotroph PAs	Non-phosphorylated RKIP binds to and inhibits Raf1 kinase and attenuates MAPK signaling	Low levels of RKIP correlate to poor clinical response to SSTs	Patients with active acromegaly	(28)
	Epidermal growth factor pathway substrate number 8 (Eps8)		Gonadotroph PAs	Increases phosphorylated ERK	Promotes proliferation and cell survival	Mouse gonadotroph LβT2 cells	(29, 30)
	TMEFF2 (transmembrane protein with EGF-like and two follistatin-likedomains)		Corticotroph PAs	Inhibits phosphorylation of AKT and ERK1/2	Decreases proliferation of corticotrope cells and reduces secretion of ACTH	AtT20 pituitary corticotrope tumor cells GH3 pituitary lactosomatotroph tumor cells	(31)
	Cold inducible RNA-binding protein (CIRP)		Corticotroph PAs	Induces cyclinD1 and decreases p27 expression via Erk1/2 signaling pathway	Promotes cells proliferation and tumor recurrence	AtT20 pituitary corticotroph cell line	(32)
	MiR-16		Non-functional PAs	Inhibits ERK/MAPK pathway activity via the suppression of MEK1 expression	Inhibits cell proliferation and induces apoptosis and cell-cycle arrest	Human HP75 tumor cells	(33)
	Mammaliansterile-20-like kinase (MST4)		Gonadotroph PAs	Activates p38 MAPK and AKT during long-term hypoxia	Increases colony formation and accelerates cell proliferation	Mouse gonadotroph LβT2 cells	(34)

PAs, pituitary adenomas. NFPAs, Non-functional pituitary adenomas.