Downregulation of HtrA1 promotes resistance to anoikis and peritoneal dissemination of ovarian cancer cells

Xiaoping He, Takayo Ota, Peng Liu, Changqing Su, Jeremy Chien, Viji Shridhar

Research output: Contribution to journalArticle

53 Citations (Scopus)

Abstract

We previously identified serine protease HtrA1 as a downregulated gene in epithelial ovarian cancer (EOC), but the functional consequence of loss of HtrA1 in EOC remains largely unclear. Here, we report that loss of HtrA1 attenuates anoikis - a critical physiologic barrier for tumor metastasis. In response to loss of anchorage, HtrA1 expression was upregulated in SKOV3 cells, resulting in autocatalytic activation of HtrA1. Stable knock-down of HtrA1 in SKOV3 and TOV21G cells resulted in resistance to anoikis due to enhanced activation of epidermal growth factor receptor (EGFR)/AKT pathway. In suspended SKOV3 cells, enhanced expression of HtrA1 inhibited EGFR/AKT pathway, leading to increased cell death, whereas protease-inactive mutant HtrA1 failed to result in either the inhibition of EGFR/AKT pathway or increased cell death, suggesting the requirement of HtrA1 protease activity in regulating anoikis. Immunoprecipitation and immunofluorescence assays revealed that HtrA1 interacted with EGFR not only on the cell membrane but also in the nucleus. Most importantly, downregulation of HtrA1 significantly enhanced the peritoneal dissemination of SKOV3ip1 cells in nonobese diabetic/severe combined immunodeficient mice, with increased phospho-EGFR level in corresponding tumor nodules compared with that in xenografts originated from the control cells. Taken together, these data reveal for the first time a novel function of HtrA1 in promoting anoikis by attenuating activation of EGFR/AKT pathway that may contribute to its metastasis suppression capacity, thus providing a possible explanation for the aggressive nature of human ovarian tumors with downregulated HtrA1.

Original languageEnglish (US)
Pages (from-to)3109-3118
Number of pages10
JournalCancer Research
Volume70
Issue number8
DOIs
StatePublished - Apr 15 2010
Externally publishedYes

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Anoikis
Epidermal Growth Factor Receptor
Ovarian Neoplasms
Down-Regulation
Peptide Hydrolases
Cell Death
Neoplasm Metastasis
Neoplasms
SCID Mice
Serine Proteases
Immunoprecipitation
Heterografts
Fluorescent Antibody Technique
Cell Membrane
Genes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Downregulation of HtrA1 promotes resistance to anoikis and peritoneal dissemination of ovarian cancer cells. / He, Xiaoping; Ota, Takayo; Liu, Peng; Su, Changqing; Chien, Jeremy; Shridhar, Viji.

In: Cancer Research, Vol. 70, No. 8, 15.04.2010, p. 3109-3118.

Research output: Contribution to journalArticle

He, Xiaoping ; Ota, Takayo ; Liu, Peng ; Su, Changqing ; Chien, Jeremy ; Shridhar, Viji. / Downregulation of HtrA1 promotes resistance to anoikis and peritoneal dissemination of ovarian cancer cells. In: Cancer Research. 2010 ; Vol. 70, No. 8. pp. 3109-3118.
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