PMID- 25273566
OWN - NLM
STAT- MEDLINE
DCOM- 20150806
LR  - 20211021
IS  - 1096-0929 (Electronic)
IS  - 1096-6080 (Print)
IS  - 1096-0929 (Linking)
VI  - 142
IP  - 2
DP  - 2014 Dec
TI  - Silencing KRAS overexpression in arsenic-transformed prostate epithelial and stem 
      cells partially mitigates malignant phenotype.
PG  - 489-96
LID - 10.1093/toxsci/kfu201 [doi]
AB  - Inorganic arsenic is a human carcinogen that likely targets the prostate. Chronic 
      arsenic exposure malignantly transforms the RWPE-1 human prostate epithelial line 
      to chronic arsenic exposed-prostate epithelial (CAsE-PE) cells, and a derivative 
      normal prostate stem cell (SC) line, WPE-stem to arsenic-cancer SCs (As-CSCs). 
      The KRAS oncogene is highly overexpressed in CAsE-PE cells and activation 
      precedes transformation, inferring mechanistic significance. As-CSCs also highly 
      overexpress KRAS. Thus, we hypothesize KRAS activation is key in causing and 
      maintaining an arsenic-induced malignant phenotype, and hence, KRAS knockdown 
      (KD) may reverse this malignant phenotype. RNA interference using shRNAmirs to 
      obtain KRAS KD was used in CAsE-PE and As-CSC cells. Cells analyzed 2 weeks post 
      transduction showed KRAS protein decreased to 5% of control after KD, confirming 
      stable KD. KRAS KD decreased phosphorylated ERK, indicating inhibition of RAS/ERK 
      signaling, a proliferation/survival pathway activated with arsenic 
      transformation. Secreted metalloproteinase (MMP) activity was increased by 
      arsenic-induced malignant transformation, but KRAS KD from 4 weeks on decreased 
      secreted MMP-9 activity by 50% in As-CSCs. Colony formation, a characteristic of 
      cancer cells, was decreased in both KRAS KD transformants. KRAS KD also decreased 
      the invasive capacity of both cell types. KRAS KD decreased proliferation in 
      As-CSCs, consistent with loss of rapid tumor growth. Genes predicted to impact 
      cell proliferation (eg, Cyclin D1, p16, and p21) changed accordingly in both KD 
      cell types. Thus, KRAS silencing impacts aspects of arsenic-induced malignant 
      phenotype, inducing loss of many typical cancer characteristics particularly in 
      As-CSCs.
CI  - Published by Oxford University Press on behalf of the Society of Toxicology 2014. 
      This work is written by US Government employees and is in the public domain in 
      the US.
FAU - Ngalame, Ntube N O
AU  - Ngalame NN
AD  - Inorganic Toxicology Group, National Toxicology Program Laboratory, Division of 
      the National Toxicology Program, National Institute of Environmental Health 
      Sciences, Research Triangle Park, North Carolina 27709.
FAU - Tokar, Erik J
AU  - Tokar EJ
AD  - Inorganic Toxicology Group, National Toxicology Program Laboratory, Division of 
      the National Toxicology Program, National Institute of Environmental Health 
      Sciences, Research Triangle Park, North Carolina 27709.
FAU - Person, Rachel J
AU  - Person RJ
AD  - Inorganic Toxicology Group, National Toxicology Program Laboratory, Division of 
      the National Toxicology Program, National Institute of Environmental Health 
      Sciences, Research Triangle Park, North Carolina 27709.
FAU - Waalkes, Michael P
AU  - Waalkes MP
AD  - Inorganic Toxicology Group, National Toxicology Program Laboratory, Division of 
      the National Toxicology Program, National Institute of Environmental Health 
      Sciences, Research Triangle Park, North Carolina 27709 waalkes@niehs.nih.gov.
LA  - eng
GR  - ES 102925/ES/NIEHS NIH HHS/United States
GR  - Intramural NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, N.I.H., Intramural
DEP - 20140930
PL  - United States
TA  - Toxicol Sci
JT  - Toxicological sciences : an official journal of the Society of Toxicology
JID - 9805461
RN  - 0 (Arsenites)
RN  - 0 (KRAS protein, human)
RN  - 0 (Proto-Oncogene Proteins)
RN  - 0 (RNA, Small Interfering)
RN  - 0 (Sodium Compounds)
RN  - 48OVY2OC72 (sodium arsenite)
RN  - EC 3.6.5.2 (Proto-Oncogene Proteins p21(ras))
RN  - EC 3.6.5.2 (ras Proteins)
SB  - IM
MH  - Animals
MH  - Arsenites/*toxicity
MH  - Cell Line, Tumor
MH  - Cell Movement/drug effects/genetics
MH  - Cell Proliferation/drug effects/genetics
MH  - Cell Transformation, Neoplastic/*drug effects/genetics
MH  - Epithelial Cells/drug effects/metabolism/*pathology
MH  - Male
MH  - Mice, Nude
MH  - Neoplastic Stem Cells/drug effects/metabolism/*pathology
MH  - Prostate/metabolism/pathology
MH  - Prostatic Neoplasms/chemically induced/*genetics/pathology
MH  - Proto-Oncogene Proteins/*genetics
MH  - Proto-Oncogene Proteins p21(ras)
MH  - *RNA Interference
MH  - RNA, Small Interfering/genetics
MH  - Sodium Compounds/*toxicity
MH  - Xenograft Model Antitumor Assays
MH  - ras Proteins/*genetics
PMC - PMC4250851
OTO - NOTNLM
OT  - KRAS
OT  - arsenic
OT  - cancer
OT  - prostate cells
OT  - shRNA
OT  - stem cells
EDAT- 2014/10/03 06:00
MHDA- 2015/08/08 06:00
PMCR- 2015/12/01
CRDT- 2014/10/03 06:00
PHST- 2014/10/03 06:00 [entrez]
PHST- 2014/10/03 06:00 [pubmed]
PHST- 2015/08/08 06:00 [medline]
PHST- 2015/12/01 00:00 [pmc-release]
AID - kfu201 [pii]
AID - 10.1093/toxsci/kfu201 [doi]
PST - ppublish
SO  - Toxicol Sci. 2014 Dec;142(2):489-96. doi: 10.1093/toxsci/kfu201. Epub 2014 Sep 
      30.