Human Noxin is an anti-apoptotic protein in response to DNA damage of A549 non-small cell lung carcinoma

Int J Cancer. 2014 Jun 1;134(11):2595-604. doi: 10.1002/ijc.28600. Epub 2013 Nov 29.

Abstract

Human Noxin (hNoxin, C11Orf82), a homolog of mouse noxin, is highly expressed in colorectal and lung cancer tissues. hNoxin contains a DNA-binding C-domain in RPA1, which mediates DNA metabolic processes, such as DNA replication and DNA repair. Expression of hNoxin is associated with S phase in cancer cells and in normal cells. Expression of hNoxin was induced by ultraviolet (UV) irradiation. Knockdown of hNoxin caused growth inhibition of colorectal and lung cancer cells. The comet assay and western blot analysis revealed that hNoxin knockdown induced apoptosis through activation of p38 mitogen-activated protein kinase (MAPK)/p53 in non-small cell lung carcinoma A549 cells. Furthermore, simultaneous hNoxin knockdown and treatment with DNA-damaging agents, such as camptothecin (CPT) and UV irradiation, enhanced apoptosis, whereas Trichostatin A (TSA) did not. However, transient overexpression of hNoxin rescued cells from DNA damage-induced apoptosis but did not block apoptosis in the absence of DNA damage. These results suggest that hNoxin may be associated with inhibition of apoptosis in response to DNA damage. An adenovirus expressing a short hairpin RNA against hNoxin transcripts significantly suppressed the growth of A549 tumor xenografts, indicating that hNoxin knockdown has in vivo anti-tumor efficacy. Thus, hNoxin is a DNA damage-induced anti-apoptotic protein and potential therapeutic target in cancer.

Keywords: DNA damage; UV; apoptosis; hNoxin; target.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis Regulatory Proteins / genetics
  • Apoptosis Regulatory Proteins / metabolism*
  • Apoptosis*
  • Biomarkers, Tumor / genetics
  • Biomarkers, Tumor / metabolism
  • Blotting, Western
  • Carcinoma, Non-Small-Cell Lung / genetics
  • Carcinoma, Non-Small-Cell Lung / metabolism
  • Carcinoma, Non-Small-Cell Lung / pathology*
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • Cell Cycle
  • Cell Cycle Proteins
  • Cell Proliferation
  • Cells, Cultured
  • Comet Assay
  • DNA Damage / physiology*
  • DNA Damage / radiation effects
  • Flow Cytometry
  • Gene Expression Profiling
  • Humans
  • In Situ Hybridization
  • Lung / cytology
  • Lung / metabolism
  • Lung Neoplasms / genetics
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / pathology*
  • Male
  • Mice
  • Mice, Nude
  • Oligonucleotide Array Sequence Analysis
  • Phosphoproteins / antagonists & inhibitors
  • Phosphoproteins / genetics
  • Phosphoproteins / metabolism*
  • RNA, Messenger / genetics
  • RNA, Small Interfering / genetics
  • Real-Time Polymerase Chain Reaction
  • Reverse Transcriptase Polymerase Chain Reaction
  • Rhodamines
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism
  • Ultraviolet Rays
  • p38 Mitogen-Activated Protein Kinases / genetics
  • p38 Mitogen-Activated Protein Kinases / metabolism

Substances

  • Apoptosis Regulatory Proteins
  • Biomarkers, Tumor
  • Carrier Proteins
  • Cell Cycle Proteins
  • DDIAS protein, human
  • Phosphoproteins
  • RNA, Messenger
  • RNA, Small Interfering
  • Rhodamines
  • TP53 protein, human
  • Tumor Suppressor Protein p53
  • noxin protein, mouse
  • lissamine rhodamine B
  • p38 Mitogen-Activated Protein Kinases