Oncogene
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Comparative Study
Wnt inhibitory factor 1 induces apoptosis and inhibits cervical cancer growth, invasion and angiogenesis in vivo.
Aberrant activation of Wingless-type (Wnt)/β-catenin signaling is widespread in human cervical cancer. However, the underlying mechanisms of Wnt activation and the therapeutic potential of Wnt inhibition remain largely unknown. Here, we demonstrate that the Wnt inhibitory factor 1 (WIF1), a secreted Wnt antagonist, is downregulated in all human primary cervical tumors and cell lines analyzed. ⋯ Our findings demonstrate for the first time that WIF1 downregulation by epigenetic gene silencing is an important mechanism of Wnt activation in cervical oncogenesis. Of major clinical relevance, we show that peritumoral WIF1 gene transfer reduces not only cancer growth but also invasion in well-established tumors. Therefore, our data provide novel mechanistic insights into the role of WIF1 in cervical cancer progression, and the important preclinical validation of WIF1 as a potent drug target in cervical cancer treatment.
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Pancreatic cancer remains as one of the most deadly cancers, and responds poorly to current therapies. The prognosis is extremely poor, with a 5-year survival of less than 5%. Therefore, search for new effective therapeutic drugs is of pivotal need and urgency to improve treatment of this incurable malignancy. ⋯ The ER stress-associated marker CHOP/GADD153 was visualized in the pancreatic tumor isolated from edelfosine-treated mice, indicating a strong in vivo ER stress response. These results suggest that edelfosine exerts its pro-apoptotic action in pancreatic cancer cells, both in vitro and in vivo, through its accumulation in the ER, which leads to ER stress and apoptosis. Thus, we propose that the ER could be a key target in pancreatic cancer, and edelfosine may constitute a prototype for the development of a new class of antitumor drugs targeting the ER.
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We integrated four gene expression profile data sets, namely two different pair-matched stage I lung adenocarcinoma data sets, secondary metastatic tumors vs benign tumors and lung tumor metastasizes to the brain, and we identified one kinase, T-LAK Cell-Originated Protein Kinase (TOPK), as a putative gene that promotes metastasis. To delineate the role of TOPK in lung cancer, we showed that overexpression of TOPK, but not a catalytically inactive form of TOPK, can enhance the migration and invasion of lung fibroblasts or cells with low TOPK expression. In addition, TOPK-induced cell migration was shown to be a PI3K/AKT-dependent event. ⋯ Moreover, an inverse correlation between TOPK and PTEN expression was present and is consistent with the biochemical findings. Finally, a combination of high TOPK and low PTEN expression was inversely correlated with overall and disease-free survivals, independent of other pathologic staging factors. Our results suggest that TOPK is a potential therapeutic target in lung cancer that promotes cell migration by modulating a PI3K/PTEN/AKT-dependent signaling pathway; they also suggest that high TOPK expression, either alone or in combination with a low level of PTEN, may serve as a prognostic marker for lung cancer.