Gas1 inhibits cell proliferation and induces apoptosis of human primary gliomas in the absence of Shh.
Growth arrest specific1 (Gas1) is a protein expressed during development and when cells arrest their growth. The potential of Gas1 as an adjuvant in the treatment of cancer, and its role as a tumor suppressor have also been proposed. In this work we are addressing the molecular mechanisms by which Gas1 induces cell arrest and apoptosis of cancer cells, using primary cultures of human gliomas as a model. We had previously demonstrated the structural relationship between Gas1 and the alpha receptors for the Glial-cell line-Derived Neurotrophic Factor (GDNF) family of ligands, and showed that Gas1 acts by inhibiting the intracellular signaling induced by GDNF. There are also reports indicating that Gas1 positively cooperates with Sonic Hedgehog (Shh) during embryonic development and in this paper we analyzed the potential interactions between Gas1 and Shh. We show that human gliomas do not express Shh, whereas GDNF and the molecular components necessary to transduce its signaling are present in human gliomas. Furthermore, the over-expression of Gas1 induces cell arrest, apoptosis and prevents the activation of Akt, a crucial mediator of survival and cellular proliferation pathways. In the present work, we present evidence demonstrating that Gas1 exerts its effects inhibiting cell growth and inducing apoptosis of glioma cells in the absence of Shh.
Domínguez-Monzón
Gabriela
G
Sección Externa de Farmacología, Centro de Investigación y de Estudios Avanzados del IPN, México, 07360 D.F., Mexico.
Benítez
Jorge A
JA
Vergara
Paula
P
Lorenzana
Rodrigo
R
Segovia
José
J
D017209:Apoptosis / Q000502:physiology*; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D049109:Cell Proliferation; D058851:GPI-Linked Proteins; D005822:Genetic Vectors; D005910:Glioma / Q000378:metabolism / Q000473:pathology; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D014161:Transduction, Genetic; D019076:Transgenes; D014407:Tumor Cells, Cultured
D018797:Cell Cycle Proteins; C096192:GAS1 protein, human; D058851:GPI-Linked Proteins; D053823:Hedgehog Proteins; D008565:Membrane Proteins; C509239:SHH protein, human; D051057:Proto-Oncogene Proteins c-akt