Mullerian inhibiting substance type II receptor as a potential target for antineoplastic therapy

Abstract

The review considers properties of the type II anti-Mullerian hormone receptor (mullerian inhibiting substance receptor type II, MISRII), a transmembrane sensor with its own serine/threonine protein kinase activity, triggering apoptosis of the Mullerian ducts in mammalian embryogenesis and providing formation of the male type reproductive system. According to recent data, MISRII overexpression in the postnatal period is found in cells of a number of ovarian, mammary gland, and prostate tumors, and anti-Mullerian hormone (AMH) has a pro-apoptotic effect on MISRII-positive tumor cells. This fact makes MISRII a potential target for targeted anti-cancer therapy. Treatment based on targeting MISRII seems to be a much more effective alternative to the traditional one and will significantly reduce the drug dose. However, the mechanism of MISRII-AMH interaction is still poorly understood, so the development of new anticancer drugs is complicated. The review analyzes MISRII molecular structure and expression levels in various tissues and cell lines, as well as current understanding of the AMH binding mechanisms and data on the possibility of using MISRII as a target for the action of AMH-based antineoplastic drugs.

The roles of anti-Müllerian hormone in breast cancer

“…AMHRII (also known as MIS receptor II) acts as a transmembrane sensor with serine/threonine protein kinase activity ( Rak et al 2019 ). It has been demonstrated that free AMH exclusively binds to AMHRII ( Mishina et al 1996 , Josso et al 2001 ), and the receptor regulates gene transcription via three mechanisms ( Rak et al 2019 ). First, when AMH binds to AMHRII, it forms a receptor complex with AMHRI.…”

“…Subsequently, intracellular Smad-proteins (R-SMads1/5/8) detach from the receptor complexes, allowing several proteins to enter the nucleus to regulate gene expression ( Josso et al 2001 , Bedenk et al 2020 ). In the nucleus, Smad proteins can either bind to DNA at Smad recognition sites (leading to transcriptional activation) or form complexes with other transcription cofactors that specifically affect the expression of target genes ( Pankhurst et al 2016 , Rak et al 2019 ). Second, binding of AMH to the type II receptor increases the content of free β-catenin in the cytoplasm, which then enters the nucleus together with lymphoid enhancer factor 1, upregulating the transcription of target genes ( Rak et al 2019 ).…”

“…In the nucleus, Smad proteins can either bind to DNA at Smad recognition sites (leading to transcriptional activation) or form complexes with other transcription cofactors that specifically affect the expression of target genes ( Pankhurst et al 2016 , Rak et al 2019 ). Second, binding of AMH to the type II receptor increases the content of free β-catenin in the cytoplasm, which then enters the nucleus together with lymphoid enhancer factor 1, upregulating the transcription of target genes ( Rak et al 2019 ). Third, the combination of AMH and AMHRII triggers the dissociation of heteromeric complexes of the nuclear factor kappa-B (NF-κB) family transcription factors (P50, P65, P52, and c-rel) and inhibitory proteins IκBα, which actuate the free transcription factors to enter the nucleus and trigger the transcription of the IER3 gene ( Rak et al 2019 ).…”

“…Second, binding of AMH to the type II receptor increases the content of free β-catenin in the cytoplasm, which then enters the nucleus together with lymphoid enhancer factor 1, upregulating the transcription of target genes ( Rak et al 2019 ). Third, the combination of AMH and AMHRII triggers the dissociation of heteromeric complexes of the nuclear factor kappa-B (NF-κB) family transcription factors (P50, P65, P52, and c-rel) and inhibitory proteins IκBα, which actuate the free transcription factors to enter the nucleus and trigger the transcription of the IER3 gene ( Rak et al 2019 ). IER3 encodes the IEX-1S factor, which is an early response protein to radiation exposure or γ-interferon or tumor necrosis factor-α ( Segev et al 2002 ).…”

“…IER3 encodes the IEX-1S factor, which is an early response protein to radiation exposure or γ-interferon or tumor necrosis factor-α ( Segev et al 2002 ). The third pathway is revealed to function in the mammary gland ( Segev et al 2000 , Rak et al 2019 ).…”