PMID- 19033662
OWN - NLM
STAT- MEDLINE
DCOM- 20081230
LR  - 20230202
IS  - 0021-9738 (Print)
IS  - 1558-8238 (Electronic)
IS  - 0021-9738 (Linking)
VI  - 118
IP  - 12
DP  - 2008 Dec
TI  - The tumor suppressor gene ARHI regulates autophagy and tumor dormancy in human 
      ovarian cancer cells.
PG  - 3917-29
LID - 35512 [pii]
LID - 10.1172/JCI35512 [doi]
AB  - The role of autophagy in oncogenesis remains ambiguous, and mechanisms that 
      induce autophagy and regulate its outcome in human cancers are poorly understood. 
      The maternally imprinted Ras-related tumor suppressor gene aplasia Ras homolog 
      member I (ARHI; also known as DIRAS3) is downregulated in more than 60% of 
      ovarian cancers, and here we show that re-expression of ARHI in multiple human 
      ovarian cancer cell lines induces autophagy by blocking PI3K signaling and 
      inhibiting mammalian target of rapamycin (mTOR), upregulating ATG4, and 
      colocalizing with cleaved microtubule-associated protein light chain 3 (LC3) in 
      autophagosomes. Furthermore, ARHI is required for spontaneous and 
      rapamycin-induced autophagy in normal and malignant cells. Although ARHI 
      re-expression led to autophagic cell death when SKOv3 ovarian cancer cells were 
      grown in culture, it enabled the cells to remain dormant when they were grown in 
      mice as xenografts. When ARHI levels were reduced in dormant cells, xenografts 
      grew rapidly. However, inhibition of ARHI-induced autophagy with chloroquine 
      dramatically reduced regrowth of xenografted tumors upon reduction of ARHI 
      levels, suggesting that autophagy contributed to the survival of dormant cells. 
      Further analysis revealed that autophagic cell death was reduced when cultured 
      human ovarian cancer cells in which ARHI had been re-expressed were treated with 
      growth factors (IGF-1, M-CSF), angiogenic factors (VEGF, IL-8), and matrix 
      proteins found in xenografts. Thus, ARHI can induce autophagic cell death, but 
      can also promote tumor dormancy in the presence of factors that promote survival 
      in the cancer microenvironment.
FAU - Lu, Zhen
AU  - Lu Z
AD  - Department of Experimental Therapeutics, University of Texas MD Anderson Cancer 
      Center, Houston, Texas 77030, USA.
FAU - Luo, Robert Z
AU  - Luo RZ
FAU - Lu, Yiling
AU  - Lu Y
FAU - Zhang, Xuhui
AU  - Zhang X
FAU - Yu, Qinghua
AU  - Yu Q
FAU - Khare, Shilpi
AU  - Khare S
FAU - Kondo, Seiji
AU  - Kondo S
FAU - Kondo, Yasuko
AU  - Kondo Y
FAU - Yu, Yinhua
AU  - Yu Y
FAU - Mills, Gordon B
AU  - Mills GB
FAU - Liao, Warren S-L
AU  - Liao WS
FAU - Bast, Robert C Jr
AU  - Bast RC Jr
LA  - eng
GR  - P01 CA064602/CA/NCI NIH HHS/United States
GR  - P50 CA098258/CA/NCI NIH HHS/United States
GR  - P01CA64602/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20081120
PL  - United States
TA  - J Clin Invest
JT  - The Journal of clinical investigation
JID - 7802877
RN  - 0 (Antibiotics, Antineoplastic)
RN  - 0 (Antirheumatic Agents)
RN  - 0 (DIRAS3 protein, human)
RN  - 0 (Intercellular Signaling Peptides and Proteins)
RN  - 0 (MAP1LC3A protein, human)
RN  - 0 (Microtubule-Associated Proteins)
RN  - 0 (Tumor Suppressor Proteins)
RN  - 886U3H6UFF (Chloroquine)
RN  - EC 2.7.- (Protein Kinases)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.1.1 (mTOR protein, mouse)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 3.4.22.- (Cysteine Endopeptidases)
RN  - EC 3.6.5.2 (rho GTP-Binding Proteins)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
CIN - J Clin Invest. 2008 Dec;118(12):3837-40. PMID: 19033653
MH  - Animals
MH  - Antibiotics, Antineoplastic/pharmacology
MH  - Antirheumatic Agents/pharmacology
MH  - *Autophagy/drug effects/genetics
MH  - Cell Line, Tumor
MH  - Cell Survival/drug effects/genetics
MH  - Chloroquine/pharmacology
MH  - Cysteine Endopeptidases/genetics/metabolism
MH  - Female
MH  - Genomic Imprinting/drug effects/genetics
MH  - Humans
MH  - Intercellular Signaling Peptides and Proteins/pharmacology
MH  - Mice
MH  - Mice, Inbred BALB C
MH  - Mice, Nude
MH  - Microtubule-Associated Proteins/genetics/metabolism
MH  - Neoplasm Transplantation
MH  - Ovarian Neoplasms/genetics/*metabolism/pathology
MH  - Phagosomes/genetics/metabolism
MH  - Phosphatidylinositol 3-Kinases/genetics/metabolism
MH  - Protein Kinases/genetics/metabolism
MH  - Sirolimus/pharmacology
MH  - TOR Serine-Threonine Kinases
MH  - Transplantation, Heterologous
MH  - Tumor Suppressor Proteins/genetics/*metabolism
MH  - rho GTP-Binding Proteins/genetics/*metabolism
PMC - PMC2582930
EDAT- 2008/11/27 09:00
MHDA- 2008/12/31 09:00
PMCR- 2008/12/01
CRDT- 2008/11/27 09:00
PHST- 2008/03/04 00:00 [received]
PHST- 2008/09/24 00:00 [accepted]
PHST- 2008/11/27 09:00 [pubmed]
PHST- 2008/12/31 09:00 [medline]
PHST- 2008/11/27 09:00 [entrez]
PHST- 2008/12/01 00:00 [pmc-release]
AID - 35512 [pii]
AID - 10.1172/JCI35512 [doi]
PST - ppublish
SO  - J Clin Invest. 2008 Dec;118(12):3917-29. doi: 10.1172/JCI35512. Epub 2008 Nov 20.