The tumor suppressor gene ARHI regulates autophagy and tumor dormancy in human ovarian cancer cells

Zhen Lu, Robert Z. Luo, Yiling Lu, Xuhui Zhang, Qinghua Yu, Shilpi Khare, Seiji Kondo, Yasuko Kondo, Yinhua Yu, Gordon Mills, Warren S L Liao, Robert C. Bast

Research output: Contribution to journalArticle

279 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)3917-3929
Number of pages13
JournalJournal of Clinical Investigation
Volume118
Issue number12
DOIs
StatePublished - Dec 1 2008
Externally publishedYes

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Autophagy
Tumor Suppressor Genes
Ovarian Neoplasms
Neoplasms
Heterografts
Sirolimus
Macrophage Colony-Stimulating Factor
Microtubule-Associated Proteins
Tumor Microenvironment
Angiogenesis Inducing Agents
Chloroquine
Interleukin-8
Phosphatidylinositol 3-Kinases
Insulin-Like Growth Factor I
Vascular Endothelial Growth Factor A
Cell Survival
Intercellular Signaling Peptides and Proteins
Carcinogenesis
Down-Regulation
Light

ASJC Scopus subject areas

  • Medicine(all)

Cite this

The tumor suppressor gene ARHI regulates autophagy and tumor dormancy in human ovarian cancer cells. / Lu, Zhen; Luo, Robert Z.; Lu, Yiling; Zhang, Xuhui; Yu, Qinghua; Khare, Shilpi; Kondo, Seiji; Kondo, Yasuko; Yu, Yinhua; Mills, Gordon; Liao, Warren S L; Bast, Robert C.

In: Journal of Clinical Investigation, Vol. 118, No. 12, 01.12.2008, p. 3917-3929.

Research output: Contribution to journalArticle

Lu, Z, Luo, RZ, Lu, Y, Zhang, X, Yu, Q, Khare, S, Kondo, S, Kondo, Y, Yu, Y, Mills, G, Liao, WSL & Bast, RC 2008, 'The tumor suppressor gene ARHI regulates autophagy and tumor dormancy in human ovarian cancer cells', Journal of Clinical Investigation, vol. 118, no. 12, pp. 3917-3929. https://doi.org/10.1172/JCI35512
Lu, Zhen ; Luo, Robert Z. ; Lu, Yiling ; Zhang, Xuhui ; Yu, Qinghua ; Khare, Shilpi ; Kondo, Seiji ; Kondo, Yasuko ; Yu, Yinhua ; Mills, Gordon ; Liao, Warren S L ; Bast, Robert C. / The tumor suppressor gene ARHI regulates autophagy and tumor dormancy in human ovarian cancer cells. In: Journal of Clinical Investigation. 2008 ; Vol. 118, No. 12. pp. 3917-3929.
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AU - Luo, Robert Z.

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AU - Zhang, Xuhui

AU - Yu, Qinghua

AU - Khare, Shilpi

AU - Kondo, Seiji

AU - Kondo, Yasuko

AU - Yu, Yinhua

AU - Mills, Gordon

AU - Liao, Warren S L

AU - Bast, Robert C.

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N2 - 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.

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.

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