TY - JOUR
T1 - BE-43547A2 exerts hypoxia-selective inhibition on human pancreatic cancer cells through targeting eEF1A1 and disrupting its association with FoxO1
AU - Liu, Can
AU - Liu, Can
AU - Liu, Guang Ju
AU - Wang, Meng Meng
AU - Jiao, Yan
AU - Sun, Yuan Jun
AU - Guo, Hui
AU - Wang, Liang
AU - Lu, Ya Xin
AU - Chen, Yue
AU - Ding, Ya Hui
N1 - Publisher Copyright:
© The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society 2025.
PY - 2025
Y1 - 2025
N2 - Hypoxia is a key feature of the tumor microenvironment that leads to the failure of many chemotherapies and induces more aggressive and resistant cancer phenotypes. Up to date, there are very few compounds and treatments that can target hypoxia. BE-43547A2 from Streptomyces sp. was one of the most hypoxia-selective compounds against PANC-1, MCF-7, and K562 cell lines. In this study, we investigated the molecular mechanism underlying the hypoxia selectivity of BE-43547A2 in human pancreatic cancer cells. We showed that BE-43547A2 displayed hypoxia-selective cytotoxicity in five pancreatic cancer cells (PANC-1, Capan-2, MIA PaCa-2, AsPC-1, and PaTu8988T) with IC50 values under hypoxia considerably lower than those under normoxia. We demonstrated that BE-43547A2 is directly bound to eEF1A1 protein in PaTu8988T cells under hypoxia. Furthermore, we revealed that hypoxia significantly elevated the expression levels of HIF1α, FoxO1, and eEF1A1 in the five pancreatic cancer cells; eEF1A1 interacted with FoxO1 in the cytoplasm, which was disrupted by BE-43547A2 followed by the nuclear translocation of FoxO1 and ultimate inhibition of JAK/STAT3 signaling pathway under hypoxia. This study reveals that BE-43547A2, targeting eEF1A1, disrupts its interaction with FoxO1 in human pancreatic cancer cells under hypoxia. This compound could serve as a potential hypoxia-selective therapy.
AB - Hypoxia is a key feature of the tumor microenvironment that leads to the failure of many chemotherapies and induces more aggressive and resistant cancer phenotypes. Up to date, there are very few compounds and treatments that can target hypoxia. BE-43547A2 from Streptomyces sp. was one of the most hypoxia-selective compounds against PANC-1, MCF-7, and K562 cell lines. In this study, we investigated the molecular mechanism underlying the hypoxia selectivity of BE-43547A2 in human pancreatic cancer cells. We showed that BE-43547A2 displayed hypoxia-selective cytotoxicity in five pancreatic cancer cells (PANC-1, Capan-2, MIA PaCa-2, AsPC-1, and PaTu8988T) with IC50 values under hypoxia considerably lower than those under normoxia. We demonstrated that BE-43547A2 is directly bound to eEF1A1 protein in PaTu8988T cells under hypoxia. Furthermore, we revealed that hypoxia significantly elevated the expression levels of HIF1α, FoxO1, and eEF1A1 in the five pancreatic cancer cells; eEF1A1 interacted with FoxO1 in the cytoplasm, which was disrupted by BE-43547A2 followed by the nuclear translocation of FoxO1 and ultimate inhibition of JAK/STAT3 signaling pathway under hypoxia. This study reveals that BE-43547A2, targeting eEF1A1, disrupts its interaction with FoxO1 in human pancreatic cancer cells under hypoxia. This compound could serve as a potential hypoxia-selective therapy.
KW - BE-43547A
KW - eEF1A1
KW - FoxO1
KW - HIF1α
KW - hypoxia-selective therapy
KW - pancreatic cancer
UR - http://www.scopus.com/inward/record.url?scp=86000235743&partnerID=8YFLogxK
U2 - 10.1038/s41401-024-01461-y
DO - 10.1038/s41401-024-01461-y
M3 - Article
C2 - 39837983
AN - SCOPUS:86000235743
SN - 0253-9756
JO - Acta Pharmacologica Sinica
JF - Acta Pharmacologica Sinica
M1 - 157
ER -