타목시펜 저항성 유방암 세포에서 MAT2A 과다발현 에 의한 S-adenosylmethionine 증가 및 병리학적 의미

Abstract

Development of acquired resistance to anti-estrogen tamoxifen (TAM) is a serious clinical problem for the treatment of breast cancer patients. Methionine adenosyltransferase (MAT) encoded by two genes MAT1A and MAT2A is a key enzyme in cellular metabolism which catalyzes the synthesis of S-adenosylmethionine (SAM). It has been also known that increase in MAT2A expression facilitates cell growth, whereas SAM controls cellular fate to growth or apoptosis. Here, we discovered that the MAT2A expression and SAM level were increased in TAM-resistant breast cancer cells (TAMR-MCF-7) cells compared to control MCF-7 cells. The enhanced expression of MAT2A in TAMR-MCF-7 cells was suppressed by NF-κB inhibition or Nrf2 knockdown. Increase in SAM with the activation of DNA methyltrasferase (DNMT) could cause an aberrant hypermethylation in gene promoter and subsequently silences gene expression. Methylation-specific PCR analyses revealed that two sites of PTEN promoters were methylated in TAMR-MCF-7 cells, which resulted in the down-regulation of PTEN expression and the increase in Akt phosphorylation. Both the loss of PTEN expression and the increased Akt phosphorylation in TAMR-MCF-7 cells were completely reversed by 5-aza-2’-deoxycytidine (5-Aza, a DNMT inhibitor). In addition, 5-Aza treatment inhibited the basal cell proliferation rate of TAMR-MCF-7 cells and intra-peritoneal injection of 5 mg/kg 5-Aza significantly suppressed TAMR-MCF-7 tumor growth in xenograft study. These results suggest that MAT2A-mediated SAM increase and methylation in PTEN promoter are potential therapeutic targets to reverse TAM resistance in breast cancer.