Activating mutations in STAT3 and STAT5 differentially affect cellular proliferation and apoptotic resistance in multiple myeloma cells.

Abstract:

:Multiple Myeloma (MM) is a progressive malignancy with poor prognosis, commonly treated by the use of the glucocorticoid Dexamethasone. Myeloma cells resist Dexamethasone induced apoptosis when exposed to IL-6 or IGF-1, both of which are known to activate several signaling cascades. For the first time, we show the actual contribution of downstream mediators, i.e., activated STAT factors, independent of the contribution of their upstream signaling pathways, on the proliferation and Dexamethasone rescue effects of IL-6 and IGF-1 in Multiple Myeloma. Retroviral transduction of cytokine dependent myeloma cells with activated STAT transcription factor constructs overcomes the cells dependence on cytokines for growth, allowing proliferation even in very low serum levels. However, the rescue of these previously cytokine dependent cells with activated STATs does not result in an increase in resistance to Dexamethasone induced apoptosis. Despite the presence of activated STAT3 and STAT5a, apoptosis is induced upon exposure to micromolar levels of Dexamethasone, and IL-6 or IGF-1 is still required to rescue the cells. The ability of these factors to block apoptosis is abrogated by the addition of PI-3 Kinase specific inhibitors, but not inhibitors that target the MAP Kinase pathway. However, ectopic expression of activated STAT3 results in partial rescue from apoptosis of cells treated with FAS ligand. Our data suggests that mechanisms of resistance to induced apoptosis and cellular proliferation are separate and distinct in cytokine dependent myeloma cells.

journal_name

Cancer Biol Ther

journal_title

Cancer biology & therapy

authors

Hodge DR,Xiao W,Wang LH,Li D,Farrar WL

doi

10.4161/cbt.3.2.621

keywords:

subject

Has Abstract

pub_date

2004-02-01 00:00:00

pages

188-94

issue

2

eissn

1538-4047

issn

1555-8576

pii

621

journal_volume

3

pub_type

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