TY - JOUR
T1 - Effects of pyrrole-imidazole polyamides targeting human TGF-β1 on the malignant phenotypes of liver cancer cells
AU - Takagi, Keiko
AU - Midorikawa, Yutaka
AU - Takayama, Tadatoshi
AU - Abe, Hayato
AU - Fujiwara, Kyoko
AU - Soma, Masayoshi
AU - Nagase, Hiroki
AU - Miki, Toshio
AU - Fukuda, Noboru
N1 - Publisher Copyright:
© 2020 by the authors.
PY - 2020/6
Y1 - 2020/6
N2 - Synthetic pyrrole-imidazole (PI) polyamides bind to the minor groove of double-helical DNA with high affinity and specificity, and inhibit the transcription of corresponding genes. In liver cancer, transforming growth factor (TGF)-β expression is correlated with tumor grade, and high-grade liver cancer tissues express epithelial-mesenchymal transition markers. TGF-β1 was reported to be involved in cancer development by transforming precancer cells to cancer stem cells (CSCs). This study aimed to evaluate the effects of TGF-β1-targeting PI polyamide on the growth of liver cancer cells and CSCs and their TGF-β1 expression. We analyzed TGF-β1 expression level after the administration of GB1101, a PI polyamide that targets human TGF-β1 promoter, and examined its effects on cell proliferation, invasiveness, and TGF-β1 mRNA expression level. GB1101 treatment dose-dependently decreased TGF-β1 mRNA levels in HepG2 and HLF cells, and inhibited HepG2 colony formation associated with downregulation of TGF-β1 mRNA. Although GB1101 did not substantially inhibit the proliferation of HepG2 cells compared to untreated control cells, GB1101 significantly suppressed the invasion of HLF cells, which displayed high expression of CD44, a marker for CSCs. Furthermore, GB1101 significantly inhibited HLF cell sphere formation by inhibiting TGF-β1 expression, in addition to suppressing the proliferation of HLE and HLF cells. Taken together, GB1101 reduced TGF-β1 expression in liver cancer cells and suppressed cell invasion; therefore, GB1101 is a novel candidate drug for the treatment of liver cancer.
AB - Synthetic pyrrole-imidazole (PI) polyamides bind to the minor groove of double-helical DNA with high affinity and specificity, and inhibit the transcription of corresponding genes. In liver cancer, transforming growth factor (TGF)-β expression is correlated with tumor grade, and high-grade liver cancer tissues express epithelial-mesenchymal transition markers. TGF-β1 was reported to be involved in cancer development by transforming precancer cells to cancer stem cells (CSCs). This study aimed to evaluate the effects of TGF-β1-targeting PI polyamide on the growth of liver cancer cells and CSCs and their TGF-β1 expression. We analyzed TGF-β1 expression level after the administration of GB1101, a PI polyamide that targets human TGF-β1 promoter, and examined its effects on cell proliferation, invasiveness, and TGF-β1 mRNA expression level. GB1101 treatment dose-dependently decreased TGF-β1 mRNA levels in HepG2 and HLF cells, and inhibited HepG2 colony formation associated with downregulation of TGF-β1 mRNA. Although GB1101 did not substantially inhibit the proliferation of HepG2 cells compared to untreated control cells, GB1101 significantly suppressed the invasion of HLF cells, which displayed high expression of CD44, a marker for CSCs. Furthermore, GB1101 significantly inhibited HLF cell sphere formation by inhibiting TGF-β1 expression, in addition to suppressing the proliferation of HLE and HLF cells. Taken together, GB1101 reduced TGF-β1 expression in liver cancer cells and suppressed cell invasion; therefore, GB1101 is a novel candidate drug for the treatment of liver cancer.
KW - Cancer stem cell
KW - Liver cancer
KW - Novel candidate drug
KW - Pyrrole-imidazole polyamide
KW - TGF-β1
UR - http://www.scopus.com/inward/record.url?scp=85087140067&partnerID=8YFLogxK
U2 - 10.3390/molecules25122883
DO - 10.3390/molecules25122883
M3 - Article
C2 - 32585841
AN - SCOPUS:85087140067
SN - 1420-3049
VL - 25
JO - Molecules
JF - Molecules
IS - 12
M1 - 2883
ER -
