TY - JOUR
T1 - Analysis of the differential effects of Interferon-alpha (IFN-α) on myeloma cell proliferation
AU - Arora, Taruna
AU - Jelinek, Diane F.
PY - 1996/12/1
Y1 - 1996/12/1
N2 - IFN-α is a commonly used chemotherapeutjc agent for the treatment of multiple myeloma. The effectiveness of IFN-a in vivo is variable, as is its anti-proliferative effects on cultured myeloma cells. The mechanism(s) accounting for this variability is not yet understood. In these studies, we have utilized two interleukin 6 (IL-6) dependent human myeloma cell lines, ANBL-6 and KAS-6/1, which are differentially regulated by IFN-a. Thus, IFN-a potently inhibits ANBL-6 growth whereas it supports significant growth by the KAS-6/1 cells. To understand these differences, we have analyzed IFN-a induced modifications in cell cycle regulatory proteins. Initial studies examined the effects of IL-6 and IFN-a on phosphorylation of the retinoblastoma protein (RB). Kinetic studies in ANBL-6 and KAS-6/1 cells revealed that a 12 hr incubation with IL-6 resulted in RB inactivation, i.e. hyperphosphorylation, in both cell lines. By contrast, IFN-a only induced RB hyperphosphorylation in the KAS-6/1 cells and was further noted to inhibit IL-6 stimulated RB hyperphosphorylation in the ANBL-6 cells. We next analyzed cell cycle molecules that lie upstream of RB. Similar studies were performed examining the effects of IFN-a on induction of cyclin D expression and CDK2/CDK4 activity. Again, IFN-a stimulation of the KAS6/1 cells increased cyclin D expression and CDK2 activity whereas IFN-a treatment of ANBL-6 cells +/- IL-6 inhibited both proteins. IFN-a , however had no effect on basal levels of CDK4 activity. These data suggest that IFN-a inhibits or stimulates myeloma cell growth by altering the functional interactions between the cyclin D-CDK2 complex and RB. Because these interactions occur in the nucleus, it is likely that the signals accounting for the differential ability of IFN-a to support myeloma cell growth lie upstream of nuclear events.
AB - IFN-α is a commonly used chemotherapeutjc agent for the treatment of multiple myeloma. The effectiveness of IFN-a in vivo is variable, as is its anti-proliferative effects on cultured myeloma cells. The mechanism(s) accounting for this variability is not yet understood. In these studies, we have utilized two interleukin 6 (IL-6) dependent human myeloma cell lines, ANBL-6 and KAS-6/1, which are differentially regulated by IFN-a. Thus, IFN-a potently inhibits ANBL-6 growth whereas it supports significant growth by the KAS-6/1 cells. To understand these differences, we have analyzed IFN-a induced modifications in cell cycle regulatory proteins. Initial studies examined the effects of IL-6 and IFN-a on phosphorylation of the retinoblastoma protein (RB). Kinetic studies in ANBL-6 and KAS-6/1 cells revealed that a 12 hr incubation with IL-6 resulted in RB inactivation, i.e. hyperphosphorylation, in both cell lines. By contrast, IFN-a only induced RB hyperphosphorylation in the KAS-6/1 cells and was further noted to inhibit IL-6 stimulated RB hyperphosphorylation in the ANBL-6 cells. We next analyzed cell cycle molecules that lie upstream of RB. Similar studies were performed examining the effects of IFN-a on induction of cyclin D expression and CDK2/CDK4 activity. Again, IFN-a stimulation of the KAS6/1 cells increased cyclin D expression and CDK2 activity whereas IFN-a treatment of ANBL-6 cells +/- IL-6 inhibited both proteins. IFN-a , however had no effect on basal levels of CDK4 activity. These data suggest that IFN-a inhibits or stimulates myeloma cell growth by altering the functional interactions between the cyclin D-CDK2 complex and RB. Because these interactions occur in the nucleus, it is likely that the signals accounting for the differential ability of IFN-a to support myeloma cell growth lie upstream of nuclear events.
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M3 - Article
AN - SCOPUS:33749128746
SN - 0892-6638
VL - 10
SP - A1460
JO - FASEB Journal
JF - FASEB Journal
IS - 6
ER -