Protein Arginine Methyltransferase (PRMT) Inhibitors—AMI-1 and SAH Are Effective in Attenuating Rhabdomyosarcoma Growth and Proliferation in Cell Cultures

Abstract

Rhabdomyosarcoma (RMS) is a malignant soft tissue cancer that develops mostly in children and young adults. With regard to histopathology, four rhabdomyosarcoma types are distinguishable: embryonal, alveolar, pleomorphic and spindle/sclerosing. Currently, increased amounts of evidence indicate that not only gene mutations, but also epigenetic modifications may be involved in the development of RMS. Epigenomic changes regulate the chromatin architecture and affect the interaction between DNA strands, histones and chromatin binding proteins, thus, are able to control gene expression. The main aim of the study was to assess the role of protein arginine methyltransferases (PRMT) in the cellular biology of rhabdomyosarcoma. In the study we used two pan-inhibitors of PRMT, called AMI-1 and SAH, and evaluated their effects on proliferation and apoptosis of RMS cells. We observed that AMI-1 and SAH reduce the invasive phenotype of rhabdomyosarcoma cells by decreasing their proliferation rate, cell viability and ability to form cell colonies. In addition, microarray analysis revealed that these inhibitors attenuate the activity of the PI3K-Akt signaling pathway and affect expression of genes related to it.

A peptoid-based inhibitor of protein arginine methyltransferase 1 (PRMT1) induces apoptosis and autophagy in cancer cells

“…This inhibitory effect is consistent with the result seen in experiments studying PRMT pan inhibitors AMI-1 and S-adenosylhomocysteine (SAH) conducted by Janisiak et al. ( 44 ) where they observed a dose-dependent decrease in cell viability of Rh30 and RD Rhabdomyosarcoma cell lines with the administration of the inhibitors.…”

Targeting epigenetic features in clear cell sarcomas based on patient-derived cell lines

“…While the viability of MUG Lucifer prim cells decreases after GSK 3368715 treatment, cytotoxicity and apoptosis increase signi cantly con rming the apoptotic effect of GSK 3368715 on MUG Lucifer prim cells. The high cytotoxicity levels could be explained by the unfavorable incubation time of six days, as cytostatic effects should not increase cytotoxicity levels [10,38]. Viability, cytotoxicity, and apoptosis, however, did not change at all in MUG Lucifer met cells after AdOx treatment.…”

“…Thus, in bone and soft tissue tumors the observed alterations in the chromatin con guration and the associated modi cations (such as methylation) appear to be related to tumorigenesis. A study in rhabdomyosarcoma cells demonstrated that the inhibition of the over-expressed protein arginine methyltransferases (PRMTs) using arginine methyltransferase inhibitor 1 (AMI-1) and S-adenosyl-I-homocysteine (SAH) led to reduced tumor growth and proliferation [10]. In another study in clear cell renal cell carcinoma, PRMT1 was shown to be suppressed by the novel PRMT1 inhibitor DCPT1061 both in vivo and in vitro.…”

The Emerging Role of PRMT6 in Cancer

“…It was observed that the expression of gene encoding PRMT6 was increased in rhabdomyosarcoma cell lines, and PRMT inhibitors (AMI-1 and SAH) effectively reduced the invasive phenotype of RMS cells by inhibiting the proliferation rate, cell viability and colony formation ability of rhabdomyosarcoma cell lines. These inhibitors also attenuate the activity of the PI3K-Akt signaling pathway, resulting in decreased levels of cyclin D1 and Bcl-xL and increased level of GADD45G protein, thus halting the cell cycle and promoting apoptosis (96). Therefore, PRMT6 is expected to be a new therapeutic target for rhabdomyosarcoma.…”