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Role of APR3 in cancer: apoptosis, autophagy, oxidative stress, and cancer therapy

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Abstract

APR3 (Apoptosis-related protein 3) is a gene that has recently been identified to be associated with apoptosis. The gene is located on human chromosome 2p22.3 and contains both transmembrane and EGF (epidermal growth factor)-like domains. Additionally, it has structural sites, including AP1, SP1, and MEF2D, that indicate NFAT (nuclear factor of activated T cells) and NF-κB (nuclear factor kappa-B) may be transcription factors for this gene. Functionally, APR3 participates in apoptosis due to the induction of mitochondrial damage to release mitochondrial cytochrome C. Concurrently, APR3 affects the cell cycle by altering the expression of Cyclin D1, which, in turn, affects the incidence and growth of malignancies and promotes cell differentiation. Previous reports indicate that APR3 is located in lysosomal membranes, where it contributes to lysosomal activity and participates in autophagy. While further research is required to determine the precise role and molecular mechanisms of APR3, earlier studies have laid the groundwork for APR3 research. There is growing evidence supporting the significance of APR3 in oncology. Therefore, this review aims to examine the current state of knowledge on the role of the newly discovered APR3 in tumorigenesis and to generate fresh insights and suggestions for future research.

Highlight

1. APR3-mediated mitochondrial damage plays a vital function in oxidative stress and apoptosis.

2. APR3 is discovered as an apoptosis-related gene and participated in cell cycle and cellular homeostasis.

3. The rivalry between NFAT and NF-κB for the binding domains of APR3 can have an impact on its transcription.

4. The expression of APR3 is increased in tumor tissues, which is expected to be an emerging disease biomarker and therapeutic target.

5. APR3 may have an integral role in nonapoptotic programmed cell death, such as autophagy, ferroptosis, cuproptosis, and pyroptosis.

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Abbreviations

APR:

Apoptosis-related protein

EGF:

Epidermal Growth Factor

NFAT:

Nuclear Factor of Activated T Cells

NF-κB:

Nuclear Factor Kappa-B

APAF-1:

Apoptotic Protease Activating Factor-1

AIF:

Apoptosis-inducing Factor

ATRA:

All-trans-retinoic Acid

CR:

Complete Remission

APL:

Acute Promyelocytic Leukemia

OXPHOS:

oxidative phosphorylation

ETC:

Electron Transfer Chain

ROS:

Reactive Oxygen Species

SNV:

Single-nucleotide Variant

AICD:

Activation-induced Cell Death

TNFα:

Tumor Necrosis Factors

CDK:

Cyclin-dependent Kinase

pRB:

Phosphorylates Retinoblastoma Protein

FOXM1:

Forkhead Box M 1

SMAD3:

SMAD Family Member 3

SKP2:

S-phase Kinase-associated Protein 2

CKS1:

cyclin-dependent kinase regulatory subunit 1

RARs:

Retinoic Acid Receptors

RXRs:

Retinoid X Receptors

9-cis-RA:

9-cis-retinoic Acid

PPAR:

Peroxisome Proliferator-activated Receptor

AML:

Acute Myelocytic Leukemia

PML:

Promyelocytic Leukemia

NQO1:

NAD(P)H Quinone Dehydrogenase 1

ARE:

Antioxidant Response Element

TCA cycle:

Tricarboxylic Acid cycle

OMM:

Outer Mitochondrial Membrane

MOMP:

Mitochondrial Outer Membrane Permeabilization

ATG proteins:

Autophagy-related proteins

ULK:

Unc-51 Like Autophagy Activating Kinase

CVT route:

Cytoplasm to Vacuole Targeting route

UBA domain:

Ubiquitin-associated domain

PtdIns3K:

Phosphatidylinositol 3-kinase

LAMP-2:

Lysosomal Associated Membrane Protein 2

NELL-1:

Neural Epidermal Growth Factor-like 1

SLC37A3:

Solute Carrier Family 37 Member 3

TSPN domain:

the N-terminal domain of thrombospondin-1

N-BP:

Nitrogen-containing-Bisphosphonates

JMD:

Juxtamembrane domain

p75NTR:

P75 Neurotrophic Receptor

JNK:

c-Jun-N-terminal kinase

ERK:

Extracellular Signal-regulated Kinase

CKS2:

Cyclin-dependent Kinase regulatorySubunit 2

ER:

Endoplasmic Reticulum

ASK1:

Apoptosis Signal-regulating Kinase 1

PTEN:

MMAC1, Mutated in Multiple Advanced Cancers 1

PI3K:

Phosphatidylinositide 3-kinases

AKT:

PKB, Protein Kinase B

TRAF2:

Tumor Necrosis Factor Receptor-associated Factor 2

AMD:

Age-related Macular Degeneration

GPX4:

Glutathione Peroxidase 4

CSTB:

Cathepsin B

NLRP3:

NOD-like receptor thermal protein domain associated protein 3

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Acknowledgements

Not applicable.

Funding

This research was supported by National Natural Science Foundation of China (Nos. 82102938, 82202429). Zhejiang Provincial Natural Science Foundation of China (Nos. LBY23H080005, LBY23H080004, LBY23H080001).

Author information

Author notes

  1. Ping Zhang and Chaoting Zhou have contributed equally to this work.

Authors and Affiliations

  1. Laboratory Medicine Center, Department of Clinical Laboratory, Zhejiang Provincial People’s Hospital(Affiliated People’s Hospital), Hangzhou Medical College, 310014, Hangzhou, Zhejiang, China

    Ping Zhang, Chaoting Zhou, Qiangan Jing, Yan Gao, Lei Yang, Jing Du, Xiangmin Tong & Ying Wang

  2. Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Department of Clinical Research Center, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, 310006, Hangzhou, Zhejiang, China

    Ping Zhang, Yanchun Li, Xiangmin Tong & Ying Wang

  3. School of Pharmacy, Hangzhou Medical College, 310000, Hangzhou, Zhejiang, China

    Ping Zhang & Yan Gao

  4. Department of Clinical Research Center, Luqiao Second People’s Hospital, 317200, Taizhou, Zhejiang, China

    Ying Wang

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Ping Zhang and Chaoting Zhou wrote the paper. Qiangan Jing, Yan Gao, Lei Yang and Yanchun Li investigated information. Jing Du, Xiangmin Tong and Ying Wang revised and finalized the manuscript. All authors read and approved the final manuscript.

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Correspondence to Jing Du, Xiangmin Tong or Ying Wang.

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Zhang, P., Zhou, C., Jing, Q. et al. Role of APR3 in cancer: apoptosis, autophagy, oxidative stress, and cancer therapy. Apoptosis 28, 1520–1533 (2023). https://doi.org/10.1007/s10495-023-01882-w

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