sp2-Iminosugar α-glucosidase inhibitor 1-C-octyl-2-oxa-3-oxocastanospermine specifically affected breast cancer cell migration through Stim1, β1-integrin, and FAK signaling pathways.
Aberrant glycosylation changes on many glycoproteins are often related to cancer progression and metastasis. sp2-Iminosugar-type castanospermine analogues, inhibitors of α-glucosidases, have been reported to exhibit antitumor activity. However, their effects on cell migration and the underlying molecular mechanism are not fully understood. Here, we investigated the effect of the pseudo-C-octyl glycoside 2-oxa-3-oxocastanospermine derivatives (CO-OCS) on breast cancer cells (MCF-7 and MDA-MB-231 cells), and MCF-10A mammary normal cell lines. We showed that CO-OCS treatment results in the drastic decrease of breast cancer cell migration without affecting cell proliferation. Furthermore, CO-OCS significantly reduced both the expression of β1-integrin, which is a crucial interacting partner of Focal Adhesion Kinase (FAK), and the phosphorylation rates of FAK and ERK1/2. CO-OCS also drastically reduced Ca2+entry through Store Operated Channels (SOC). Orai1 and Stim1, two N-glycosylated proteins, are involved in Store-Operated Calcium Entry (SOCE), and are essential for breast tumor cell migration. Our results showed that CO-OCS decreased the expression, at the protein level, of Stim1 without affecting that of Orai1. Moreover, cell migration and SOCE were attenuated by CO-OCS as well as when Stim1 was silenced. In contrast, in MCF-10A cells, CO-OCS slightly reduced cell migration, but was without effect on gene expression of Stim1, Orai1, β1-integrin, or FAK and ERK1/2 activation. Our results provide strong evidence for a significant effect of CO-OCS on breast cancer cell migration and support that this effect was associated with β1-integrin, Stim1, and FAK signaling pathways.
Laboratory of Cellular and Molecular Physiology (EA 4667), SFR CAP-SANTE (FED 4132), UFR of Sciences, Amiens, France.
Nahla
N
Gueder
Laboratory of Cellular and Molecular Physiology (EA 4667), SFR CAP-SANTE (FED 4132), UFR of Sciences, Amiens, France.
Ghada
G
Allan
Laboratory of Cellular and Molecular Physiology (EA 4667), SFR CAP-SANTE (FED 4132), UFR of Sciences, Amiens, France.
Marie-Sophie
MS
Telliez
Laboratory of Cellular and Molecular Physiology (EA 4667), SFR CAP-SANTE (FED 4132), UFR of Sciences, Amiens, France.
Frédéric
F
Hague
Instituto de Investigaciones Químicas (IIQ), CSIC-Universidad de Sevilla, Americo Vespucio 49, Isla de la Cartuja, Sevilla, Spain.
José M
JM
Fernandez
Facultad de Química, Departamento de Química Orgánica, Universidad de Sevilla, Sevilla, Spain.
Elena M
EM
Sanchez-Fernandez
Facultad de Química, Departamento de Química Orgánica, Universidad de Sevilla, Sevilla, Spain.
Carmen
C
Ortiz-Mellet
Laboratory of Cellular and Molecular Physiology (EA 4667), SFR CAP-SANTE (FED 4132), UFR of Sciences, Amiens, France.|Faculty of Sciences, Department of Biology, Ibn Zohr University, Agadir, Morocco.
Ahmed
A
Ahidouch
Laboratory of Cellular and Molecular Physiology (EA 4667), SFR CAP-SANTE (FED 4132), UFR of Sciences, Amiens, France.
Halima
H
Ouadid-Ahidouch
D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D002465:Cell Movement / Q000187:drug effects*; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D051417:Focal Adhesion Kinase 1 / Q000378:metabolism*; D065089:Glycoside Hydrolase Inhibitors / Q000494:pharmacology*; D006031:Glycosylation; D006801:Humans; D007212:Indolizines / Q000493:pharmacokinetics*; D019012:Integrin beta1 / Q000378:metabolism*; D061986:MCF-7 Cells; D009361:Neoplasm Invasiveness; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D034622:RNA Interference; D015398:Signal Transduction / Q000187:drug effects; D000071737:Stromal Interaction Molecule 1 / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D014162:Transfection
C000622955:1-C-octyl-2-oxa-3-oxocastanospermine; D065089:Glycoside Hydrolase Inhibitors; D007212:Indolizines; D019012:Integrin beta1; D009363:Neoplasm Proteins; C103530:STIM1 protein, human; D000071737:Stromal Interaction Molecule 1; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human; D048049:Extracellular Signal-Regulated MAP Kinases
Stim1 and Orai1; breast cancer; calcium; glycosylation; migration