Prolactinomas are among the most common intracranial tumours. Prolactin secretion can lead to menstrual and lactation disorders in women and a decline in sexual function in men, and the incidence in women is significantly higher than that in men. Prolactin microadenomas with clinical symptoms generally do not develop into macroadenomas, and some prolactinomas are aggressive, with enlarged tumours and elevated blood prolactin levels [
1]. Dopamine agonists (DAs), such as bromocriptine, are first-line treatment drugs. Most prolactinoma patients show a good response to bromocriptine treatment, but 20% of patients display serious drug resistance. The patients took bromocriptine for 3 months, but their serum prolactin did not return to normal levels, and the tumour volume was reduced by less than 50% [
2‐
4]. DA resistance in prolactinoma patients is becoming increasingly serious and severely affects human reproductive health. Therefore, it is a clinical problem that urgently needs to be resolved.
Prolactinoma cells express DA receptors, and DA(s) can effectively inhibit prolactin secretion and shrink tumours by binding to DA receptors on the surface of most patients’ cells. As a result, a decrease in D2 receptor expression levels will cause the failure of DAs to inhibit prolactin and further lead to DA resistance in prolactinoma [
5]. Studies have shown that the reduction of dopamine D2 receptor expression is considered to be the main cause of DA resistance in prolactinoma [
6‐
8], but DRD2-mediated resistance cannot explain all the issues. Therefore, it is urgent to explore the mechanism of drug resistance in prolactinoma.
Mitogen-activated protein kinases (MAPKs) include the MAPK/ERK family or classical pathway and the Big MAP kinase-1 (BMK-1), c-Jun N-terminal kinase (JNK), and p38 signalling families. The activation cascade occurs in the following order: MAPKKK (mitogen-activated protein kinase kinase kinases, represented by RAF and its variants), followed by MAPK kinase (MAPKK: MEK1/2/3/4/5/6/7), and finally MAPK. The mitogen-activated protein kinase (MAPK) cascade is a critical pathway for human cancer cell survival, dissemination, and resistance to drug therapy [
9,
10]. p38 MAPK includes isoforms p38α, p38β, p38γ, and p38δ. Mammalian p38 kinases share more than 60% amino acid sequence identity, with p38α being 75% identical to p38β and p38γ being 75% identical to p38δ. Moreover, p38α and p38β are ubiquitously expressed, p38α usually at higher levels than p38β except in some brain regions, whereas p38γ and p38δ expression tends to be more tissue-specific, p38γ (MAPK12/ERK6) in muscle, and p38δ (MAPK13/SAPK4) in lung and kidney [
11].p38 demonstrates distinct and even opposing effects in different cancers, as it was shown to serve either as a tumor suppressor or tumor promoter. It was also shown that in some cases, it can perform both activities in different stages of cancer development. Although all p38 isoforms have been implicated in the processes listed above, they can be divided into two somewhat distinct subgroups: p38α and p38β (p38α/β) versus p38γ and p38δ. p38β is very similar in amino acid sequence to p38α. They have similar substrate specificities and are sensitive to the same chemical inhibitors, suggesting that p38β and p38α may have overlapping functions [
12‐
14]. Indeed, p38α/β were implicated in the induction and maintenance of several pathologies such as inflammation, cancer, and autoimmune diseases, but also hypertrophy, hypoxic nephropathy, and diabetes. In many cases, the role of p38α/β is not direct, but it is mediated by p38α/β-regulated inflammation, which in turn contributes to the development of the diseases [
15]. It is now clear that p38γ and p38δ play crucial roles in inflammation, the development of insulin resistance, neurotoxicity, cell growth, and the progression of tumour formation. Abnormal activity and dysregulation of the p38α/β cascade are associated with a variety of diseases [
16].. Activation of the p38 MAPK signalling pathway promotes the occurrence and progression of various tumours, which is responsible for the signal transduction of many chemotherapy drugs and is a necessity for multidrug resistance induced by anticancer drugs in tumour cells. Inhibition of p38 can increase the sensitivity of cisplatin-induced apoptosis in human lung cancer cells and colon cancer cells. Compared with cisplatin alone, the combined administration of cisplatin and p38 inhibitors can significantly inhibit tumour cell proliferation and induce apoptosis [
17,
18]. p38 MAPK is involved in cell apoptosis, and the transcription factor NF-κB prevents cell apoptosis by inducing the expression of several antiapoptotic proteins. Changes in genes and proteins that control cell apoptosis are one of the mechanisms underlying multidrug resistance in tumours [
19‐
23]. The p38 MAPK signalling pathway plays an important role in the occurrence and development of the pituitary, and there are multiple potential targets in its treatment [
24]. Our previous study found that MAPK14 is highly expressed in prolactinoma and can be suppressed by the inhibition of MAPK14 [
25]. The mechanism of MAPK11/12/13/14 in bromocriptine resistance in prolactinoma has not been investigated. Therefore, we studied the effects of bromocriptine on MAPK11, MAPK12, MAPK13, and MAPK14 in rat prolactinoma, compared the difference in the effect of bromocriptine on MAPK11, MAPK12, MAPK13, MAPK14, NF-κB, p65, Bcl2, and Bax in DA-resistant GH3 cells and DA-sensitive MMQ cells, and further evaluated the therapeutic effects of bromocriptine after the reduction of p38 MAPK in GH3 cells. These findings clarify the exact mechanism of the four p38 MAPK subunits in bromocriptine-resistant prolactinomas.