Open AccessInhibition of the Hexosamine Biosynthetic Pathway by targeting PGM3 causes breast cancer growth arrest and apoptosis
Author(s) -
Francesca Ricciardiello,
Giuseppina Votta,
Roberta Palorini,
Isabella Raccagni,
Laura Brunelli,
Alice Paiotta,
Francesca Tinelli,
Giuseppe D’Orazio,
Silvia Valtorta,
Luca De Gioia,
Roberta Pastorelli,
Rosa María Moresco,
Barbara La Ferla,
Ferdinando Chiaradonna
Publication year - 2018
Publication title -
cell death and disease
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.482
H-Index - 111
ISSN - 2041-4889
DOI - 10.1038/s41419-018-0405-4
Subject(s) - breast cancer , cancer research , cancer , triple negative breast cancer , cancer cell , apoptosis , cell growth , intracellular , biology , glycosylation , programmed cell death , microbiology and biotechnology , medicine , biochemistry
Cancer aberrant N - and O -linked protein glycosylation, frequently resulting from an augmented flux through the Hexosamine Biosynthetic Pathway (HBP), play different roles in tumor progression. However, the low specificity and toxicity of the existing HBP inhibitors prevented their use for cancer treatment. Here we report the preclinical evaluation of FR054, a novel inhibitor of the HBP enzyme PGM3, with a remarkable anti-breast cancer effect. In fact, FR054 induces in different breast cancer cells a dramatic decrease in cell proliferation and survival. In particular, in a model of Triple Negative Breast Cancer (TNBC) cells, MDA-MB-231, we show that these effects are correlated to FR054-dependent reduction of both N - and O -glycosylation level that cause also a strong reduction of cancer cell adhesion and migration. Moreover we show that impaired survival of cancer cells upon FR054 treatment is associated with the activation of the Unfolded Protein Response (UPR) and accumulation of intracellular ROS. Finally, we show that FR054 suppresses cancer growth in MDA-MB-231 xenograft mice, supporting the advantage of targeting HBP for therapeutic purpose and encouraging further investigation about the use of this small molecule as a promising compound for breast cancer therapy.