Vorinostat induced cellular stress disrupts the p38 mitogen activated protein kinase and extracellular signal regulated kinase pathways leading to apoptosis in Waldenström macroglobulinemia cells

Abstract

Histone deacetylases (HDACs) are aberrantly expressed, and inhibitors of HDACs induce apoptosis in lymphoplasmacytic cells (LPCs) in Waldenström macroglobulinemia (WM). The molecular profile by which these agents induce apoptosis in WM LPCs remains to be delineated. We examined the activity of the histone deacetylase inhibitor, vorinostat, and dissected its pro-apoptotic pathways in WM LPCs. Vorinostat induced apoptosis in WM cells through activating specific caspases at varying times. Inhibitors of apoptosis (IAPs) were down-regulated after vorinostat treatment. Cellular stress induced in vorinostat-treated WM cells was reflected by changes in the mitogen activated protein kinase (MAPK) pathways. Activated phospho-p38 MAPK was up-regulated at 12 h, while phospho-extracellular signal-regulated kinase (Erk) abruptly decreased at 24 h. Bortezomib did not augment vorinostat induced primary WM cell killing as reported in other B-cell disorders. These studies support that stress induced apoptosis in vorinostat-treated WM LPCs is mediated through disrupting the activity of the Erk and p38 MAPK pathways.

Waldenström macroglobulinemia: What a hematologist needs to know

“…Vorinostat, an HDAC inhibitor, is shown to induce apoptosis of WM cells via downregulation of the cytoprotective MAPK ERK1/2 and inhibitors of apoptosis (IAP) family of proteins and activation of multiple caspases, proapoptotic MAPKs, and JNK [135]. Another HDAC inhibitor, LBH589 (panobinostat) has been shown to inhibit bone marrow stromal cell-triggered or IL-6-and IGF-1-induced proliferation of a WM cell line.…”

Screening and identification of a novel FHL2 mutation by whole exome sequencing in twins with familial Waldenström macroglobulinemia

“…Different studies have unraveled the interconnections between FHL2 and a number of signaling cascades, including WNT, TNF‐α, MAPK, TGF‐β, androgen receptor, AP1, CREB/CREM, E4F1, and EpCAM 38‐47 . Furthermore, WM cells have been reported to be associated with the WNT/β‐catenin pathway and the ERK/MAPK pathway 21,48 . Thus, mutated FHL2 might contribute to WNT/β‐catenin or ERK/MAPK modulation in WM cells.…”

“…[38][39][40][41][42][43][44][45][46][47] Furthermore, WM cells have been reported to be associated with the WNT/β-catenin pathway and the ERK/ MAPK pathway. 21,48 Thus, mutated FHL2 might contribute to WNT/β-catenin or ERK/MAPK modulation in WM cells. Also, PPI analysis has shown that FHL2 may interact with IL-6 and HCK, which previously have been confirmed to have a significant pathogenic effect in WM.…”