Prohibitin (PHB) expression is associated with aggressiveness in DLBCL and flavagline-mediated inhibition of cytoplasmic PHB functions induces anti-tumor effects

Abstract

BackgroundDiffuse large B-cell lymphomas (DLBCLs) are aggressive lymphomas accounting for approximately a third of non-Hodgkin lymphomas. Prohibitin 1 (PHB1) and prohibitin 2 (PHB2) are scaffold proteins that promote mitochondria homeostasis and consequently cell survival, but biological functions of cytoplasmic PHBs remain largely unknown in DLBCL.MethodsPHB expression was analyzed in 82 DLBCL biopsies and five DLBCL cell lines by immunohistochemistry (IHC) and Western blotting. Pharmacological inhibition of PHB using the synthetic flavagline FL3 was realized in vitro to gain insight PHB cellular functions. Effects of FL3 on DLBCL cell line viability, apoptosis, C-Raf-ERK–MNK–eIF4E signaling pathway and eIF4F complex formation and activity were evaluated by XTT assay, annexin V-FITC/PI dual staining and Western blotting respectively. Subcutaneous DLBCL xenograft model in SCID mice was also performed to determine in vivo FL3 effect.ResultsAs in DLBCL cell lines, PHB1 and PHB2 were expressed in germinal center B-cell–like (GCB) and activated B-cell–like (ABC) subtypes. In patient samples, high PHB levels were associated with higher serum LDH (PHB1 and PHB2), IPIaa (PHB2), and Ki-67 (PHB2) expression. Higher PHB1 expression tends to be associated with shorter event-free survival (EFS) in patients, especially in male patients. FL3 induced apoptosis of DLBCL cell lines that was associated with inhibition of the ERK-MNK-eIF4E signaling pathway, including aggressive double/triple-hit DLBCL cell lines. This resulted in altered eIF4F complex formation and activity leading to a reduction of Bcl-2 and c-Myc expression levels. Moreover, FL3 strongly downregulated DLBCL cellular levels of Akt protein and AKT mRNA. FL3 antitumor activity was also confirmed in vivo in a murine xenograft model.ConclusionOur data indicate that PHB overexpression is associated with markers of tumor aggressiveness in DLBCL, and that targeting PHBs may be a therapeutic option, notably in aggressive subtypes.

Prohibitin 2 is Involved in Parkin-Mediated Mitophagy in Urothelial Cells of Cattle Infected with Bovine Papillomavirus

“…Very likely, PHB2 and other prohibitins will represent the topics of specific interest in next future as further details in PHB2 biology will contribute to gain insights into unexplored mitophagy mechanisms and virus infections. A further exciting research area will be to highlight PHB2 as an important target which may be useful in diagnosis and therapy of PHB-dependent diseases, including viral diseases [ 15 , 17 ].…”

“…Furthermore, it has been suggested that PHB2 is required for cholestasis-induced mitophagy, wherein PHB2 recruits LC3 to the damaged mitochondria via interaction with p62/SQSTM1 and LC3 [ 16 ]. Recently, PHB2 overexpression has been shown to be associated with aggressiveness in diffuse large B-cell lymphomas and targeting PHBs may have a therapeutic potential, notably in the aggressive subtypes [ 17 ]. PHBs are believed to be play a crucial a role in the pathogenesis of virus infection.…”

Aberrant Expression of Prohibitin Is Related to Prognosis of Nasal Extranodal Natural Killer/T Cell Lymphoma, Nasal Type

“…In human hematopoietic tissue tumors, overexpression of PHB is detected in the mitochondria, and PHB improves cell survival under oxygen stress [22]. Cytoplasmic PHB expression levels in diffuse large B-cell lymphoma cells are positively associated with serum LDH, PHB2, and Ki-67 expression, and tend to be inversely linked to event-free survival [12]. Our results revealed that the cytoplasmic PHB expression levels of nasal ENKTCL cells are inversely correlated to OS.…”

“…In the nucleus, PHB controls the cell cycle, cell proliferation, and cell apoptosis by interacting with cell cycle-regulated proteins, transcription factors, and apoptosis-associated proteins [8][9][10]. The abnormal expression of PHB is closely associated with the development and progression of a number of human cancers [11][12][13][14]. The role of PHB in the development of nasal ENKTCL remains unknown.…”

Deeping in the Role of the MAP-Kinases Interacting Kinases (MNKs) in Cancer

“…MNK inhibition by FL3, a synthetic flavagine and ligand of PHBs, determined antitumor activities in vitro and in vivo by inhibiting MNK-dependent eIF4E phosphorylation. This MNK1 inhibition reduced Bcl-2 and c-Myc expression, inducing apoptosis that would allow the treatment of rituximab resistant diseases [109].…”