Cyclic nucleotide Response Element Binding protein (CREB) activation promotes survival signal in human K562 erythroleukemia cells exposed to ionising radiation/etoposide combined treatment.
Anticancer therapy addresses the destruction of tumour cells which try to counteract the effect of drugs and/or ionising radiation. Thus the knowledge of the threshold over which the cells do not resist such agents could help in the setting up of therapy protocols. Since a key role was assigned to Cyclic nucleotide Response Element Binding protein (CREB) multigenic family (which is composed of several nuclear transcription factors involved in c-AMP signalling in cell differentiation, proliferation, apoptosis, survival and adaptive response and in hematopoiesis and acute leukemias), attention was paid to the activation of Erk cascade and of the downstream kinases and transcription factors such as p90RSK and CREB. K562 erythroleukemia cell survival to 1.5 Gy ionising radiation with or without etoposide treatment seemed to involve Erk phosphorylation which, regulating p90 RSK, should activate CREB. In parallel, p38 MAP kinase activity down-modulation, along with low caspase-3 activity, and no modification of Bax and Bcl2 levels, supported such evidence. Thus, endogenous CREB activation, triggering a potent survival signal in K562 cells exposed to 1.5 Gy with or without etoposide, led us to suggest that using specific inhibitors against CREB, such as modified phosphorothionate oligodeoxynucleotides (ODN) corresponding to CREB-1 sequence, anticancer therapy efficacy could be improved.
Cataldi
Amelia
A
Dipartimento di Biomorfologia, Universitá G.D'Annunzio, Italy. cataldi@unich.it
di Giacomo
Viviana
V
Rapino
Monica
M
Genovesi
Domenico
D
Rana
Rosa Alba
RA
D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage; D050882:CREB-Binding Protein / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects* / Q000502:physiology / Q000528:radiation effects*; D003131:Combined Modality Therapy; D004305:Dose-Response Relationship, Drug; D004307:Dose-Response Relationship, Radiation; D005047:Etoposide / Q000008:administration & dosage*; D006801:Humans; D020014:K562 Cells; D011829:Radiation Dosage; D011836:Radiation Tolerance / Q000187:drug effects / Q000528:radiation effects; D011839:Radiation, Ionizing; D015398:Signal Transduction / Q000187:drug effects / Q000528:radiation effects
D000972:Antineoplastic Agents, Phytogenic; D005047:Etoposide; D050882:CREB-Binding Protein; C494363:CREBBP protein, human