Sialyltransferase Inhibitors Suppress Breast Cancer Metastasis

Chih Wei Fu; Han En Tsai; Wei Sheng Chen; Tzu Ting Chang; Chia Ling Chen; Pei Wen Hsiao; Wen Shan Li

doi:10.1021/acs.jmedchem.0c01477

Sialyltransferase Inhibitors Suppress Breast Cancer Metastasis

Chih Wei Fu, Han En Tsai, Wei Sheng Chen, Tzu Ting Chang, Chia Ling Chen, Pei Wen Hsiao, Wen Shan Li

Research output: Contribution to journal › Article › peer-review

21 Citations (Scopus)

Abstract

We report the synthesis and evaluation of a series of cell-permeable and N- versus O-selective sialyltransferase inhibitors. Inhibitor design entailed the functionalization of lithocholic acid at C(3) and at the cyclopentane ring side chain. Among the series, FCW34 and FCW66 were shown to inhibit MDA-MB-231 cell migration as effectively as ST3GALIII-gene knockdown did. FCW34 was shown to inhibit tumor growth, reduce angiogenesis, and delay cancer cell metastasis in animal models. Furthermore, FCW34 inhibited vessel development and suppressed angiogenic activity in transgenic zebrafish models. Our results provide clear evidence that FCW34-induced sialyltransferase inhibition reduces cancer cell metastasis by decreasing N-glycan sialylation, thus altering the regulation of talin/integrin/FAK/paxillin and integrin/NFκB signaling pathways.

Original language	English
Pages (from-to)	527-542
Number of pages	16
Journal	Journal of Medicinal Chemistry
Volume	64
Issue number	1
DOIs	https://doi.org/10.1021/acs.jmedchem.0c01477
Publication status	Published - Jan 14 2021
Externally published	Yes

ASJC Scopus subject areas

Molecular Medicine
Drug Discovery

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1021/acs.jmedchem.0c01477

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title = "Sialyltransferase Inhibitors Suppress Breast Cancer Metastasis",

abstract = "We report the synthesis and evaluation of a series of cell-permeable and N- versus O-selective sialyltransferase inhibitors. Inhibitor design entailed the functionalization of lithocholic acid at C(3) and at the cyclopentane ring side chain. Among the series, FCW34 and FCW66 were shown to inhibit MDA-MB-231 cell migration as effectively as ST3GALIII-gene knockdown did. FCW34 was shown to inhibit tumor growth, reduce angiogenesis, and delay cancer cell metastasis in animal models. Furthermore, FCW34 inhibited vessel development and suppressed angiogenic activity in transgenic zebrafish models. Our results provide clear evidence that FCW34-induced sialyltransferase inhibition reduces cancer cell metastasis by decreasing N-glycan sialylation, thus altering the regulation of talin/integrin/FAK/paxillin and integrin/NFκB signaling pathways.",

author = "Fu, {Chih Wei} and Tsai, {Han En} and Chen, {Wei Sheng} and Chang, {Tzu Ting} and Chen, {Chia Ling} and Hsiao, {Pei Wen} and Li, {Wen Shan}",

note = "Publisher Copyright: {\textcopyright} 2020 American Chemical Society.",

year = "2021",

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doi = "10.1021/acs.jmedchem.0c01477",

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T1 - Sialyltransferase Inhibitors Suppress Breast Cancer Metastasis

AU - Fu, Chih Wei

AU - Tsai, Han En

AU - Chen, Wei Sheng

AU - Chang, Tzu Ting

AU - Chen, Chia Ling

AU - Hsiao, Pei Wen

AU - Li, Wen Shan

PY - 2021/1/14

Y1 - 2021/1/14

N2 - We report the synthesis and evaluation of a series of cell-permeable and N- versus O-selective sialyltransferase inhibitors. Inhibitor design entailed the functionalization of lithocholic acid at C(3) and at the cyclopentane ring side chain. Among the series, FCW34 and FCW66 were shown to inhibit MDA-MB-231 cell migration as effectively as ST3GALIII-gene knockdown did. FCW34 was shown to inhibit tumor growth, reduce angiogenesis, and delay cancer cell metastasis in animal models. Furthermore, FCW34 inhibited vessel development and suppressed angiogenic activity in transgenic zebrafish models. Our results provide clear evidence that FCW34-induced sialyltransferase inhibition reduces cancer cell metastasis by decreasing N-glycan sialylation, thus altering the regulation of talin/integrin/FAK/paxillin and integrin/NFκB signaling pathways.

AB - We report the synthesis and evaluation of a series of cell-permeable and N- versus O-selective sialyltransferase inhibitors. Inhibitor design entailed the functionalization of lithocholic acid at C(3) and at the cyclopentane ring side chain. Among the series, FCW34 and FCW66 were shown to inhibit MDA-MB-231 cell migration as effectively as ST3GALIII-gene knockdown did. FCW34 was shown to inhibit tumor growth, reduce angiogenesis, and delay cancer cell metastasis in animal models. Furthermore, FCW34 inhibited vessel development and suppressed angiogenic activity in transgenic zebrafish models. Our results provide clear evidence that FCW34-induced sialyltransferase inhibition reduces cancer cell metastasis by decreasing N-glycan sialylation, thus altering the regulation of talin/integrin/FAK/paxillin and integrin/NFκB signaling pathways.

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Sialyltransferase Inhibitors Suppress Breast Cancer Metastasis

Abstract

ASJC Scopus subject areas

UN SDGs

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