TLE1 Regulates Anoikis
Brunquell and colleagues found that the Groucho-related TLE1 corepressor protein is a novel survival pathway that is activated by breast cancer cells in the absence of cell-substrate attachment. Importantly, the nuclear TLE1 protein is channelled to cytoplasm and targeted for degradation by the caspase-independent apoptotic effector Bit1 protein during anoikis (detachment-induced apoptosis). These observed molecular events provided mechanistic insight underlying the Bit1 anoikis pathway, which the authors have previously shown to be uniquely regulated by integrin-mediated cell attachment. Given the role of TLE1 in the anoikis resistance of breast cancer cells, inhibition of the TLE1 pathway may serve as a novel therapeutic strategy in combating breast cancer aggressiveness and metastatic disease through restoration of tumor cell anoikis sensitivity. The data also suggest a novel mechanism by which breast cancer cells evade anoikis via TLE1 expression, which is regulated downstream of matrix attachment.
XCR1 in Ovarian Carcinoma Title
Mechanisms underlying metastatic epithelial ovarian carcinoma (MEOC) are not well understood. Expression and function of the lymphotactin receptor (XCR1), a potentially drug-targetable protein of the G protein-coupled receptor family, was investigated to validate it as a future target against MEOC. It was found that XCR1 is expressed in the majority of primary and metastatic EOCs. Activated lymphotactin axis was able to support EOC cell proliferation and migration. Reduction of XCR1 expression in EOC cells prevented metastasis on common sites, such as diaphragm and peritoneal wall. These results indicate that XCR1 may be a potential target against MEOC.
CDC25 Opposes ATM Activity during Development
Zebrafish standstill mutant embryos exhibit developmental defects and cell-cycle abnormalities. Verduzco and colleagues used positional cloning to show that standstill encodes zebrafish cdc25a, a key cell-cycle regulator. Unexpectedly, they found that genetic or pharmacologic inhibition of ATM kinase can rescue the cell-cycle effects of cdc25a deficiency. The DNA damage response pathway is critically important in cancer biology and treatment, but there has been little exploration of its functions in early embryogenesis. This work establishes a new role of cdc25a to balance constitutive activity of the ATM-mediated DNA damage response pathway during vertebrate development.
Patched Functions in Multidrug Transport
Hedgehog signaling is involved in cancer development and metastasis. The receptor Patched is a Hedgehog target gene that is overexpressed in many tumors that develop drug resistance and disease recurrence. Bidet and colleagues demonstrate a link between Patched and resistance to chemotherapy and provide new insight into Patched function. Data show that the expression of human Patched in yeast conferred resistance to several chemotherapeutic agents such as doxorubicin and that inhibition of Patched expression increased doxorubicin accumulation in different cancer cell lines. Patched targeting therapy should be a promising strategy to overcome the resistance of cancer to chemotherapeutic treatment.
- ©2012 American Association for Cancer Research.