IL-24 Induces Apoptosis of Chronic Lymphocytic Leukemia B Cells Engaged into the Cell Cycle through Dephosphorylation of STAT3 and Stabilization of p53 Expression

Abstract

Chronic lymphocytic leukemia (CLL) is characterized by the accumulation of long-lived monoclonal B cells mostly arrested at the G0/G1 phase of the cell cycle. CLL cells strongly express intracellular melanoma differentiation-associated gene-7 (MDA7)/IL-24. However, adenovirus-delivered MDA7 was reported to be cytotoxic in several tumor cell lines. We report herein that rIL-24 alone had no effect; however, sequential incubation with rIL-2 and rIL-24 reduced thymidine incorporation by 50% and induced apoptosis of CLL cells in S and G2/M phases of the cell cycle, but not of normal adult blood or tonsil B cells. IL-24 stimulated STAT3 phosphorylation in IL-24R1-transfected cells but not in normal or CLL B cells. In contrast, IL-24 reversed the IL-2-induced phosphorylation of STAT3 in CLL, and this effect was neutralized by anti-IL-24 Ab. Phospho- (P)STAT3 inhibition induced by IL-24 was reversed by pervanadate, an inhibitor of tyrosine phosphatases. The addition of rIL-24 to IL-2-activated CLL B cells resulted in increases of transcription, protein synthesis. and phosphorylation of p53. The biological effects of IL-24 were reversed by the p53 inhibitor pifithrin-α and partly by the caspase inhibitor zvad. Troglitazone (a protein tyrosine phosphatase, PTP1B activator) phosphatase inhibited PSTAT3 and augmented p53 expression. PSTAT3 is a transcriptional repressor of p53, and therefore IL-24 induction of p53 secondary to PSTAT3 dephosphorylation may be sensed as a stress signal and promote apoptosis in cycling cells. This model explains why IL-24 can protect some resting/differentiated cells and be deleterious to proliferating cells.

Activation of p53 Promotes Renal Injury in Acute Aristolochic Acid Nephropathy

“…This is similar to a previous finding that IL-24 induces apoptosis of chronic lymphocytic leukemia B cells through a mechanism of dephosphorylation of STAT3 and stabilization of p53 expression by phosphorylating p53 (Ser15). 22 In this study, AA induced TEC apoptosis by activating the p53 pathway via inactivation of the p53 repressor STAT3. Addition of AA also induces the dephosphorylation of STAT3, leading to stabilization of p53 by increasing p53 (Ser15) phosphorylation and protein accumulation.…”

“…22 Addition of AA (5 g/ml) caused dephosphorylation of phospho-STAT3 (Tyr705), thereby reducing STAT3 protein expression in a time-and dosage-dependent manner (Figure 10). The functional role of phospho-STAT3 in protecting AA-mediated TEC apoptosis via the p53 pathway was further demonstrated by the finding that overexpression of STAT3 in TECs rescued AA-induced (5 g/ml) dephosphorylation of STAT3, thereby inhibiting AA-induced p53 phosphorylation and p53 protein accumulation and p53-mediated apoptosis demonstrated by cleaved caspase-3 and TUNEL ϩ TECs (Figure 11).…”

IL-24 Transgenic Mice: In Vivo Evidence of Overlapping Functions for IL-20, IL-22, and IL-24 in the Epidermis

“…The results from IL-24 Tg mice further confirmed that IL-24 is a classic cytokine like IL-20 and IL-22. Although it is possible that IL-24 may induce growth arrest or apoptosis for certain types of cells in vitro (21,22), the postnatal lethality and psoriatic skin phenotype as a result of hyperplasia in the epidermis observed for IL-24 Tg mice raise potential serious safety issues for using IL-24 (also known as MDA-7 before it was shown as a cytokine) as an anticancer agent in gene therapy (1,23).…”

Dysregulation of Apoptosis and Proliferation in CLL Cells

“…Interleukin 13, another cytokine involved in B lymphocytes activation, impedes leukemic cells apoptosis induced by interleukin 2 in vitro (Chaouchi et al, 1996). Interleukin 24 triggers apoptosis in CLL cells recruited to the cell cycle, by the inactivation of STAT3 kinase thus stabilizing expression of p53 (Sainz-Perez et al, 2008).…”