Alterations in the expression of MHC class I glycoproteins by B16BL6 melanoma cells modulate insulin receptor-regulated signal transduction and augment [correction of augments] resistance to apoptosis.
In a variety of malignancies, the immune-escape phenotype is associated, in part, with the inability of tumor cells to properly present their Ags to CTLs due to a deranged expression of MHC class I glycoproteins. However, these molecules were found to possess broader nonimmune functions, including participation in signal transduction and regulation of proliferation, differentiation, and sensitivity to apoptosis-inducing factors; processes, which are characteristically impaired during malignant transformation. We investigated whether the deranged expression of MHC class I expression by tumor cells could affect proper receptor-mediated signal transduction and accentuate their malignant phenotype. The malignant and H-2K murine MHC class I-deficient B16BL6 melanoma cells were characterized by an attenuated capacity to bind insulin due to the retention of corresponding receptor in intracellular stores. The restoration of H-2K expression in these cells, which abrogated their capacity to form tumors in mice, enhanced membrane translocation of the receptor, presumably, by modulating its glycosylation. The addition of insulin to H-2K-expressing melanoma cells cultured in serum-free conditions precluded apoptotic death by up-regulating the activity of protein kinase B (PKB)/Akt. In contrast, the deficiency for H-2K characteristic to the malignant clones was associated with a constitutive high activity of PKB/Akt, which rendered them resistant to apoptosis, induced by deprivation of serum-derived growth factors. The possibility to correct the regulation of PKB/Akt activity by restoration of H-2K expression in B16BL6 melanoma cells may be considered as an attractive approach for cancer therapy, since an aberrant activation of this enzyme is characteristic to resistant malignancies.
Assa-Kunik
Efrat
E
Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.
Fishman
Daniel
D
Kellman-Pressman
Sigal
S
Tsory
Sylvia
S
Elhyany
Shira
S
Baharir
Ofer
O
Segal
Shraga
S
D000276:Adjuvants, Immunologic / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D017209:Apoptosis / Q000276:immunology*; D045744:Cell Line, Tumor; D002999:Clone Cells; D006023:Glycoproteins / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D006031:Glycosylation; D006133:Growth Substances / Q000172:deficiency; D006183:H-2 Antigens / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D007113:Immunity, Innate; D007328:Insulin / Q000378:metabolism; D008546:Melanoma, Experimental / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D011485:Protein Binding / Q000276:immunology; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D011972:Receptor, Insulin / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000276:immunology*
D000276:Adjuvants, Immunologic; D006023:Glycoproteins; D006133:Growth Substances; D006183:H-2 Antigens; D007328:Insulin; D011518:Proto-Oncogene Proteins; D011972:Receptor, Insulin; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt