ABSTRACT
Acute promyelocytic leukemia (APL) is characterized by a reciprocal translocation between chromosomes 15 and 17, t(15;17), resulting in the expression of PML-RARα fusion protein, which disrupts the normal PML nuclear bodies (PML-NBs) to micro-speckled pattern, leading to loss of their original functions. Moreover, reformation of PML-NBs in APL by arsenic is considered as one of the important step for APL treatment. Leptomycin B (LMB), a nuclear export inhibitor, is commonly used to inhibit the proteins exporting from the nucleus to the cytoplasm. In the present study, we found that LMB could induce the reformation of PML-NBs in leukemia NB4 cells as well as in APL blast cells from the patients, implying that nuclear shuttle proteins might be involved in the reformation of PML-NBs. Herein, we further found that LMB totally lost the ability to induce PML-NBs reformation when the endogenous PML gene was knocked out, indicating that endogenous PML protein is probably involved in the reformation of PML-NBs. More interestingly, among all PML isoforms (i.e., seven isoforms), reformation of PML-NBs was only observed when co-transfection of PML-RARα with PML-I after LMB treatment. Similarly, deletion of nuclear export signal (NES) of PML-I could also reform PML-NBs, suggesting that the protein level of endogenous PML-I in nucleus is important for the reformation of PML-NBs that interfered by PML-RARα fusion protein. Additionally, LMB has synergistic effect with iAsIII on enhancing PML-RARα fusion protein degradation, and it might provide new insight into APL treatment at clinical level in the near future.
Subject(s)
Antineoplastic Agents/pharmacology , Leukemia, Promyelocytic, Acute/drug therapy , Oncogene Proteins, Fusion/metabolism , Promyelocytic Leukemia Protein/metabolism , Antineoplastic Agents/therapeutic use , Arsenic Trioxide/pharmacology , Arsenic Trioxide/therapeutic use , Cell Line, Tumor , Cell Nucleus/drug effects , Cell Nucleus/metabolism , Cell Nucleus/pathology , Drug Screening Assays, Antitumor , Drug Synergism , Fatty Acids, Unsaturated/pharmacology , Fatty Acids, Unsaturated/therapeutic use , Humans , Leukemia, Promyelocytic, Acute/blood , Leukemia, Promyelocytic, Acute/genetics , Leukemia, Promyelocytic, Acute/pathology , Leukocytes, Mononuclear , Oncogene Proteins, Fusion/genetics , Primary Cell Culture , Protein Isoforms/metabolism , Proteolysis/drug effectsABSTRACT
PLZF-RARα is the second most frequent variant acute promyelocytic leukemia (APL) fusion protein that ranks after PML-RARα in APL. However, PLZF-RARα is resistant to current front line APL treatments including all transretinoic acid (ATRA), arsenic trioxide (ATO), and chemotherapy (i.e., Idarubicin). Herein, we for the first time report that phenylarsine oxide (PAO) could effectively induce PLZF-RARα variant fusion protein degradation through ubiquitin proteasome degradation pathway by apoptosis, which indicates that PAO might be a potential candidate for the treatment of PLZF-RARα variant APL. Given that, this study highlights the potential benefit of arsenic-organometallic compound PAO in APL treatment.
Subject(s)
Arsenicals/pharmacology , Leukemia, Promyelocytic, Acute/drug therapy , Oncogene Proteins, Fusion/antagonists & inhibitors , HeLa Cells , Humans , Leukemia, Promyelocytic, Acute/metabolism , Oncogene Proteins, Fusion/metabolismABSTRACT
Bacterial infection causes enhanced reactive oxygen species (ROS) levels in insects. Oxidation resistance 1 (OXR1) plays an antioxidant role in eukaryotic organisms, including insects. In this report, we demonstrated that Pseudomonas aeruginosa and Staphylococcus aureus infection and hydrogen peroxide (H2 O2 ) injection induced the expression of specific transcriptional isoforms of OXR1 in larval silkworms. We further showed that a Jun kinase (JNK) pathway inhibitor, SP600125, down-regulated expression of OXR1 during infection, leading to elevated H2 O2 levels in the hemolymph, resulting in lower viability of the injected bacteria inside the silkworm larvae. Our study suggests that OXR1 participates in protecting larval silkworms from oxidative stress and bacterial infection through the JNK pathway.
