ABSTRACT
The stomatin/prohibitin/flotillin/HflK/HflC (SPFH) domain is present in an evolutionarily conserved family of proteins that regulate a myriad of signaling pathways in archaea, bacteria and eukaryotes. The most studied SPFH proteins, prohibitins, have already been targeted by different families of small molecules to induce anticancer, cardioprotective, anti-inflammatory, antiviral, and antiosteoporotic activities. Ligands of other SPFH proteins have also been identified and shown to act as anesthetics, anti-allodynia, anticancer, and anti-inflammatory agents. These findings indicate that modulators of human or bacterial SPFH proteins can be developed to treat a wide variety of human disorders.
Subject(s)
Bacterial Proteins/antagonists & inhibitors , Small Molecule Libraries/pharmacology , Disease , Humans , Ligands , Molecular Structure , Small Molecule Libraries/chemistryABSTRACT
Over the last three decades, the scaffold proteins prohibitins-1 and -2 (PHB1/2) have emerged as key signaling proteins regulating a myriad of signaling pathways in health and diseases. Small molecules targeting PHBs display promising effects against cancers, osteoporosis, inflammatory, cardiac and neurodegenerative diseases. This review provides an updated overview of the various classes of PHB ligands, with an emphasis on their mechanism of action and therapeutic potential. We also describe how these ligands have been used to explore PHB signaling in different physiological and pathological settings.
Subject(s)
Heart Diseases/pathology , Ligands , Neoplasms/therapy , Nervous System Diseases/therapy , Osteoporosis/therapy , Repressor Proteins/metabolism , Gene Expression , Heart Diseases/metabolism , Heart Diseases/therapy , Humans , Neoplasms/metabolism , Neoplasms/pathology , Nervous System Diseases/metabolism , Nervous System Diseases/pathology , Osteoporosis/metabolism , Osteoporosis/pathology , Prohibitins , Protein Processing, Post-Translational , Repressor Proteins/chemistry , Repressor Proteins/genetics , Signal TransductionABSTRACT
The scaffold proteins prohibitins-1 and 2 (PHB1/2) play many important roles in coordinating many cell signaling pathways and represent emerging targets in cardiology and oncology. We previously reported that a family of natural products derivatives, flavaglines, binds to PHB1/2 to exert cardioprotectant and anti-cancer effects. However, flavaglines also target the initiation factor of translation eIF4A, which doesn't contribute to cardioprotection and may even induce some adverse effects. Herein, we report the development of a convenient and robust synthesis of the new PHB2 ligand 2'-phenylpyrrolidinyl-spirooxindole, and its analogues. We discovered that these compounds displays cardioprotective effect against doxorubicin mediated cardiotoxicity and uncovered the structural requirement for this activity. We identified in particular some analogues that are more cardioprotectant than flavaglines. Pull-down experiments demonstrated that these compounds bind not only to PHB2 but also PHB1. These novel PHB ligands may provide the basis for the development of new drugs candidates to protect the heart against the adverse effects of anticancer treatments.
Subject(s)
Cardiotonic Agents/pharmacology , Drug Discovery , Myocytes, Cardiac/drug effects , Oxindoles/pharmacology , Repressor Proteins/antagonists & inhibitors , Spiro Compounds/pharmacology , Apoptosis/drug effects , Cardiotonic Agents/chemical synthesis , Cardiotonic Agents/chemistry , Cell Line , Cell Survival/drug effects , Dose-Response Relationship, Drug , Doxorubicin/antagonists & inhibitors , Doxorubicin/pharmacology , Humans , Ligands , Molecular Structure , Myocytes, Cardiac/metabolism , Oxindoles/chemical synthesis , Oxindoles/chemistry , Prohibitins , Repressor Proteins/metabolism , Spiro Compounds/chemical synthesis , Spiro Compounds/chemistry , Structure-Activity RelationshipABSTRACT
BACKGROUND: Diffuse 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. METHODS: PHB 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. RESULTS: As 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. CONCLUSION: Our 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.
