Pathophysiological significance of N‐myc downstream‐regulated gene 2 in cancer development through protein phosphatase 2A phosphorylation regulation

Lim

2021

Cells

N-myc downstream-regulated gene 2 (NDRG2) is a tumor suppressor gene that increases tumor sensitivity to anticancer drugs, slows tumor progression, and inhibits metastasis. NDRG2 is suppressed in various aggressive tumor positions, whereas NDRG2 expression is associated with patient prognosis, such as an improved survival rate. In this review, we summarize the tumor suppressor mechanism of NDRG2 and provide information on the function of NDRG2 concerning the susceptibility of cells to apoptosis. NDRG2 increases the susceptibility to apoptosis in various physiological environments of cells, such as development, hypoxia, nutrient deprivation, and cancer drug treatment. Although the molecular and cell biological mechanisms of NDRG2 have not been fully elucidated, we provide information on the mechanisms of NDRG2 in relation to apoptosis in various environments. This review can assist the design of research regarding NDRG2 function and suggests the potential of NDRG2 as a molecular target for cancer patients.

Section: Sensitivity To Anticancer Drugs and Ndrg2mentioning

confidence: 99%

N-myc Downstream-Regulated Gene 2 (NDRG2) Function as a Positive Regulator of Apoptosis: A New Insight into NDRG2 as a Tumor Suppressor

Lim

2021

Cells

“…1 We previously reported that the aberrant activation of several signal transduction pathways in HTLV-1-infected T cells plays an important role in the development of HTLV-1-associated diseases. [2][3][4][5] Moreover, the constitutive activation of the JAK/STAT signaling pathway is involved in the progression and development of ATL-and HTLV-1-infected diseases. Although the molecular mechanism of the activated JAK/STAT signaling pathway has not yet been completely elucidated in ATL, the persistent phosphorylation of JAK1, JAK2, and JAK3 through the autocrine pathways of IL-2/IL-2R and the collapse of the dephosphorylation system lead to the subsequent entry of phosphorylated STAT1, STAT3, and STAT5 into the nucleus, resulting in the upregulation of downstream target genes that are involved in processes such as cell proliferation (Cyclin D), inhibition of apoptosis (Bcl-2, Bcl-xL), and inflammation (IL-1β, IL-6, and IFNγ).…”

Section: Introductionmentioning

confidence: 99%

“…We previously reported that the aberrant activation of several signal transduction pathways in HTLV‐1‐infected T cells plays an important role in the development of HTLV‐1‐associated diseases 2–5 . Moreover, the constitutive activation of the JAK/STAT signaling pathway is involved in the progression and development of ATL‐ and HTLV‐1‐infected diseases.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of adult T‐cell leukemia cell proliferation by polymerized proanthocyanidin from blueberry leaves through JAK proteolysis

Ichikawa

Sugamoto

Matsuura³

et al. 2022

Cancer Science

Self Cite

We have previously reported that the proanthocyanidin (PAC) fraction of blueberry leaf extract (BB-PAC) inhibits the proliferation of HTLV-1-infected adult T-cell leukemia (ATL) by inducing apoptosis. In the present study, we further analyzed the structure of BB-PAC and elucidated the molecular mechanism underlying the inhibitory function of HTLV-1-infected and ATL cells. After hot water extraction with fractionation with methanol-acetone, BB-PAC was found to be concentrated in fractions 4 to 7 (Fr7). The strongest inhibition of ATL cell growth was observed with Fr7, which contained the highest BB-PAC polymerization degree of 14. The basic structure of BB-PAC is mainly B-type bonds, with A-type bonds (7.1%) and cinchonain I units as the terminal unit (6.1%). The molecular mechanism of cytotoxicity observed around Fr7 against ATL cells was the degradation of JAK1 to 3 and the dephosphorylation of STAT3/5, which occurs by proteasome-dependent proteolysis, confirming that PAC directly binds to heat shock protein 90 (HSP90). JAK degradation was caused by proteasome-dependent proteolysis, and we identified the direct binding of PAC to HSP90. In addition, the binding of cochaperone ATPase homolog 1 (AHA1) to HSP90, which is required for activation of the cofactor HSP90, was inhibited by BB-PAC treatment. Therefore, BB-PAC inhibited the formation of the HSP90/AHA1 complex and promoted the degradation of JAK protein due to HSP90 dysfunction. These results | 1407ICHIKAWA et Al.

“…In adult T-cell leukemia (ATL), PP2A has been reported to negatively regulate PRMT5 through the dephosphorylation of S355. This interaction is mediated by N-MYC downstream regulated gene (NDRG2), which acts as an adaptor between PRMT5 and PP2A ( 120 , 121 ). When NDRG2 expression is low, PRMT5 is reported to promote cell growth and prevent apoptosis ( 120 ).…”

Section: Interplay Of Pp2a and Chromatin Remodeling Complexesmentioning

confidence: 99%

PP2A and cancer epigenetics: a therapeutic opportunity waiting to happen

Tinsley

Allen-Petersen

2022

NAR Cancer

The epigenetic state of chromatin is altered by regulators which influence gene expression in response to environmental stimuli. While several post-translational modifications contribute to chromatin accessibility and transcriptional programs, our understanding of the role that specific phosphorylation sites play is limited. In cancer, kinases and phosphatases are commonly deregulated resulting in increased oncogenic signaling and loss of epigenetic regulation. Aberrant epigenetic states are known to promote cellular plasticity and the development of therapeutic resistance in many cancer types, highlighting the importance of these mechanisms to cancer cell phenotypes. Protein Phosphatase 2A (PP2A) is a heterotrimeric holoenzyme that targets a diverse array of cellular proteins. The composition of the PP2A complex influences its cellular targets and activity. For this reason, PP2A can be tumor suppressive or oncogenic depending on cellular context. Understanding the nuances of PP2A regulation and its effect on epigenetic alterations can lead to new therapeutic avenues that afford more specificity and contribute to the growth of personalized medicine in the oncology field. In this review, we summarize the known PP2A-regulated substrates and potential phosphorylation sites that contribute to cancer cell epigenetics and possible strategies to therapeutically leverage this phosphatase to suppress tumor growth.