Strategies of treating cancer by cytokine regulation of chromosome end remodelling.
1. Telomeres (ends of chromosomes) undergo constant remodelling during cell development, proliferation and differentiation, as well as in neoplastic cell immortalization and transformation. How the cellular microenvironment influences telomere remodelling (lengthening or shortening) remains largely unknown. 2. Recently, studies from our laboratories and others have indicated that growth factors and cytokines have significant roles in regulating telomere remodelling and thus influence cell functions and properties. Cancer cells must maintain their already short telomeres either by the enzyme telomerase or, more rarely, through alternative lengthening of telomeres, which functions independently of cellular regulation. 3. However, application of transforming growth factor-beta family cytokines induces transcriptional inhibition of telomerase in cancer cells, leading to telomere shortening, cell senescence (ageing) and apoptosis (death) by mechanisms dependent on telomerase inhibition. Furthermore, selective gene silencing of vascular endothelial growth factor and/or the telomerase catalytic subunit (i.e. telomerase reverse transcriptase) potently inhibits the growth of cervical cancer and laryngeal squamous cancer in mice. 4. The present paper summarizes our current understanding of the negative regulation by cytokines of telomere maintenance and thus cancer cell proliferation in cultured cells and mouse models.
Liu
Jun-Ping
JP
Molecular Signalling Laboratory, Department of Immunology, Monash University Central Clinical School, Melbourne, Victoria, Australia. ping.liu@med.monash.edu.au
Nicholls
Craig
C
Chen
Shi-Ming
SM
Li
He
H
Tao
Ze-Zhang
ZZ
D000818:Animals; D055419:Bone Morphogenetic Protein 7 / Q000378:metabolism; D002455:Cell Division / Q000235:genetics*; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D055808:Drug Discovery / Q000379:methods*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008954:Models, Biological; D009369:Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism; D019098:Telomerase / Q000235:genetics; D016615:Telomere / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000235:genetics*
D055419:Bone Morphogenetic Protein 7; D016207:Cytokines; D016212:Transforming Growth Factor beta; C509186:TERT protein, human; D019098:Telomerase