Identification of XAF1 as a novel cell cycle regulator through modulating G2/M checkpoint and interaction with checkpoint kinase 1 in gastrointestinal cancer

Jide Wang, Qing Gu, Ming Li, Wenjing Zhang, Mo Yang, Bing Zou, Shing Chan, Liang Qiao, Bo Jiang, Shuiping Tu, Juan Ma, Ivan F. Hung, Hui Yao Lan, Benjamin C.Y. Wong

Research output: Contribution to journalArticlepeer-review

28 Scopus citations

Abstract

Background and aims: X-linked inhibitor of apoptosis-associated factor 1 (XAF1) was first recognized as an antagonist of X-linked inhibitor of apoptosis in suppressing caspase 3 activity. It has lower expression in cancer cells than normal tissue. Overexpression of XAF1 can inhibit cancer cell growth and sensitize tumor necrosis factor-related apoptosis-inducing ligand- or etoposide-induced apoptosis. The aim of this study is to elucidate the mechanism of XAF1 in regulating cell growth. Methods: Stable transfectants of gastrointestinal (GI) cancer cell lines AGS and SW1116 expressing XAF1 and vector control were generated. Cell growth, apoptosis, mitotic status and cell cycle distribution were assessed. The interaction between XAF1 and G2/M checkpoint proteins was evaluated by immunoblotting, kinase assay and co-immunoprecipitation assay. Mitotic catastrophe was identified by occurrence of aberrant nuclei and centrosomal amplification. Results: Our results showed that overexpression of XAF1 suppressed serum-dependent cancer cell growth, induced mitotic catastrophe and G2/M cell cycle arrest. Interestingly, XAF1 was predominantly expressed in G2/M phase after cell cycle synchronization. XAF1 interacted with and activated checkpoint kinase 1 (Chk1), inactivated Cdc25C and lead to inactivation of Cdc2-cyclin B complex. Suppression of Chk1 abrogated XAF1-induced G2/M arrest. Conclusions: Our findings implicate XAF1 as a novel cell cycle modulator that is recruited in G2/M phase and thus unravel a novel function pathway of XAF1, suggesting the potential role of XAF1 as the target for the management of GI cancers.

Original languageEnglish (US)
Pages (from-to)1507-1516
Number of pages10
JournalCarcinogenesis
Volume30
Issue number9
DOIs
StatePublished - 2009
Externally publishedYes

Bibliographical note

Funding Information:
Simon KY Lee Endowed Professorship Fund; Gordon Chiu Stomach Cancer Research Fund; Outstanding Researcher Award 2005–2006; University of Hong Kong; Dean Grant of Nanfang Hospital, Southern Medical University, China.

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