Induction of G1 arrest in glioma cells by T11TS is associated with upregulation of Cip1/Kip1 and concurrent downregulation of cyclin D (1 and 3).
In our laboratory, a novel therapeutic probe, T11TS, a membrane glycoprotein, was isolated which had antineoplastic activity against experimental glioma. Development of a novel therapeutic strategy with T11TS has unearthed a newer dimension of its mechanism of action: modulation of the cell cycle. In this study, we have presented evidence to support the finding that T11TS induces G1 cell cycle arrest of rat glioma cells. Results of flow cytometric studies showed that the treatment produced a marked increase in the proportion of cells in the G1 phase. Flow cytometry, immunoblotting, immunoprecipitation, and kinase assays were performed for investigating the involvement of G1 cell cycle regulators. T11TS induces downregulation of the cyclin-D (1 and 3) expression with the concurrent upregulation of p21 and p27 and their concomitant association with cyclin-dependent kinase 4, proliferating cell nuclear antigen and cyclin E respectively leading to a decrease in cyclin-dependent kinase 4 kinase activity. A transient rise in retinoblastoma protein level and coordinated binding of retinoblastoma protein with E2F coincided with the accumulation of cells in G1 phase. Thus, our observations have uncovered an antiproliferative pathway for T11TS, causing retardation of glioma cell cycle.
Acharya
Sagar
S
Department of Laboratory Medicine, School of Tropical Medicine, Kolkata, West Bengal, India.
Chatterjee
Sirshendu
S
Kumar
Pankaj
P
Bhattacharjee
Malabika
M
Chaudhuri
Suhnrita
S
Chaudhuri
Swapna
S
D000818:Animals; D000831:Animals, Newborn; D000970:Antineoplastic Agents / Q000302:isolation & purification / Q000494:pharmacology*; D001932:Brain Neoplasms / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D056741:Cyclin D / Q000096:biosynthesis*; D019938:Cyclin D1 / Q000096:biosynthesis; D056743:Cyclin D3 / Q000096:biosynthesis; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000096:biosynthesis*; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000096:biosynthesis*; D015536:Down-Regulation; D004910:Erythrocyte Membrane / Q000737:chemistry; D005038:Ethylnitrosourea; D005260:Female; D005434:Flow Cytometry; D016193:G1 Phase / Q000187:drug effects*; D005910:Glioma / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D006023:Glycoproteins / Q000302:isolation & purification / Q000494:pharmacology*; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D012756:Sheep; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
D000970:Antineoplastic Agents; C530106:Ccnd1 protein, rat; C534698:Ccnd3 protein, rat; D056741:Cyclin D; D056743:Cyclin D3; D050759:Cyclin-Dependent Kinase Inhibitor p21; D006023:Glycoproteins; D019938:Cyclin D1; D050760:Cyclin-Dependent Kinase Inhibitor p27; D005038:Ethylnitrosourea