Inhibition of PP2A activity by H2O2 during mitosis disrupts nuclear envelope reassembly and alters nuclear shape

Abstract

Many types of cancer cells exhibit abnormal nuclear shapes induced by various molecular changes. However, whether reactive oxygen species (ROS) induce nuclear deformation has not been fully addressed. Here, we show that hydrogen peroxide (H 2 O 2 ) treatment induced concentration-dependent alterations in nuclear shape that were abolished by pretreatment with the antioxidant N-acetyl-L-cysteine or by catalase overexpression. Interestingly, treatment with H 2 O 2 induced nuclear shape alterations significantly more frequently in mitotic cells than in asynchronous cells, suggesting that H 2 O 2 mainly affects nuclear envelope disassembly and/or reassembly processes. Because protein phosphatase 2 A (PP2A) activity is reported to be involved in nuclear envelope reassembly during mitosis, we investigated the possible involvement of PP2A. Indeed, H 2 O 2 reduced the activity of PP2A, an effect that was mimicked by the PP1 and PP2A inhibitor okadaic acid. Moreover, overexpression of PP2A but not PP1 or PP4 partially rescued H 2 O 2 -induced alterations in nuclear shape, indicating that the decrease in PP2A activity induced by H 2 O 2 is specifically involved in the observed nuclear shape alterations. We further show that treatment of mitotic cells with H 2 O 2 induced the mislocalization of BAF (barrier-to-autointegration factor), a substrate of PP2A, during telophase. This effect was associated with Lamin A/C mislocalization and was rescued by PP2A overexpression. Collectively, our findings suggest that H 2 O 2 preferentially affects mitotic cells through PP2A inhibition, which induces the subsequent mislocalization of BAF and Lamin A/C during nuclear envelope reassembly, leading to the formation of an abnormal nuclear shape.

TSC22D4 interacts with Akt1 to regulate glucose metabolism

“…H 2 O 2 impairs protein phosphatase 2A (PP2A) activity, which is responsible for removing Akt phosphorylations on T308 and S473 (19)(20)(21)(22). In agreement with these earlier studies, we also observed that H 2 O 2 treatment promoted Akt phosphorylation (Fig.…”

Hyperosmolality in CHO culture: Effects on cellular behavior and morphology

“…We suppose that nuclear shape alterations in CHO cells are probably a direct result of osmotically induced stress. A recent finding reveals that exposure to elevated ROS concentrations induces nuclear shape alterations including fragmentation and folding due to aberrations in the reassembly of the nuclear envelope in cancer cells (Ahn et al, 2019). The authors discovered that the cells are most vulnerable during mitosis, so it is unclear if the structures we observed on Days 6 and 8 in the "feed" condition are artifacts of uncompleted mitotic division disrupted by osmolality increase on Day 3/4 or if these have evolved during the fed-batch gradually with time.…”

A study on UHPLC-MS/MS analyses of DNA and RNA oxidative damage metabolites in patients with cervical carcinoma: 8-oxoG in urine as a potential biomarker of cervical carcinoma

“…Excessive ROS may damage important cellular components and lead to defects in DNA repair mechanism and antioxidant defense system, thus changing cell homeostasis [ 2 ]. ROS have influences on cell proliferation, the imbalance of cell growth and tumorigenesis, which also play important roles in growth factors, mitosis, and development of cancers [ 3 , 4 , 5 ]. However, nucleic acids are often transformed into various modified bases when exposed to oxygen free radicals.…”