Anti-cancer properties of glucosamine-hydrochloride in YD-8 human oral cancer cells: Induction of the caspase-dependent apoptosis and down-regulation of HIF-1α.
Evidence suggests anti-tumor activities of glucosamine-hydrochloride (GS-HCl). In the present study, we investigated anti-proliferative, growth suppressive and/or pro-apoptotic effects of GS-HCl on YD-8 human oral squamous cell carcinoma (OSCC) cells. Fundamentally, treatment with GS-HCl strongly inhibited proliferation and induced apoptosis in YD-8 cells, as determined by MTS and DNA fragmentation analyses. Of further note, as measured by Western analyses, GS-HCl treatment led to activation of caspase-3, cytosolic accumulation of cytochrome c, down-regulation of Mcl-1 and HIF-1α, up-regulation of GRP78, an indicator of ER stress, and generation of ROS in YD-8 cells. Importantly, results of pharmacological inhibition studies showed that treatment with z-VAD-fmk, a pan-caspase inhibitor, but not with vitamin E, an anti-oxidant strongly blocked the GS-HCl-induced apoptosis in YD-8 cells. Analyses of additional cell culture works further revealed that GS-HCl had a strong growth suppressive effect on not only YD-8 but also YD-10B and YD-38, two other human OSCC cell lines. These findings collectively demonstrate that GS-HCl has anti-proliferative, anti-survival, and pro-apoptotic effects on YD-8 cells and the effects appear to be mediated via mechanisms associated with the mitochondrial-dependent activation of caspases, down-regulation of Mcl-1, and induction of ER stress. Considering HIF-1α as a tumor angiogenic transcription factor, the ability of GS-HCl to down-regulate HIF-1α in YD-8 cells may further support its anti-cancer property. It is thus suggested that GS-HCl may be used as a potential anti-cancer drug against human OSCC.
Department of Oral and Maxillofacial Surgery, School of Dentistry, Kyungpook National University, Daegu 700-412, Republic of Korea.
Chang-Wook
CW
Jung
Jeong-Rang
JR
Jo
Sang-Han
SH
Lee
Yu-Kyoung
YK
Park
Nak-Kyun
NK
Jung
Dae-Kyu
DK
Song
JaeHoon
J
Bae
Ki-Young
KY
Nam
Jung-Sook
JS
Ha
In-Sook
IS
Park
Gy-Young
GY
Park
Byeong-Churl
BC
Jang
Jong-Wook
JW
Park
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002294:Carcinoma, Squamous Cell / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D045304:Cytochromes c / Q000378:metabolism; D053938:DNA Fragmentation; D015536:Down-Regulation; D000091342:Endoplasmic Reticulum Chaperone BiP; D005944:Glucosamine / Q000494:pharmacology*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D009062:Mouth Neoplasms / Q000378:metabolism; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
D000970:Antineoplastic Agents; D000091342:Endoplasmic Reticulum Chaperone BiP; C497442:HIF1A protein, human; C000717247:HSPA5 protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2; D017382:Reactive Oxygen Species; D045304:Cytochromes c; D053148:Caspase 3; D005944:Glucosamine