title: The anoikis effector Bit1 displays tumor suppressive function in lung cancer cells.
abstract: The mitochondrial Bit1 (Bcl-2 inhibitor of transcription 1) protein is a part of an apoptotic pathway that is uniquely regulated by integrin-mediated attachment. As an anoikis effector, Bit1 is released into the cytoplasm following loss of cell attachment and induces a caspase-independent form of apoptosis. Considering that anoikis resistance is a critical determinant of transformation, we hypothesized that cancer cells may circumvent the Bit1 apoptotic pathway to attain anchorage-independence and tumorigenic potential. Here, we provide the first evidence of the tumor suppressive effect of Bit1 through a mechanism involving anoikis induction in human lung adenocarcinoma derived A549 cells. Restitution of Bit1 in anoikis resistant A549 cells is sufficient to induce detachment induced-apoptosis despite defect in caspase activation and impairs their anchorage-independent growth. Conversely, stable downregulation of Bit1 in these cells significantly enhances their anoikis resistance and anchorage-independent growth. The Bit1 knockdown cells exhibit significantly enhanced tumorigenecity in vivo. It has been previously shown that the nuclear TLE1 corepressor is a putative oncogene in lung cancer, and we show here that TLE1 blocks Bit1 mediated anoikis in part by sequestering the pro-apoptotic partner of Bit1, the Amino-terminal Enhancer of Split (AES) protein, in the nucleus. Taken together, these findings suggest a tumor suppressive role of the caspase-independent anoikis effector Bit1 in lung cancer. Consistent with its role as a tumor suppressor, we have found that Bit1 is downregulated in human non-small cell lung cancer (NSCLC) tissues.
authors.affiliation: Department of Biology, Xavier University of Louisiana, New Orleans, Louisiana, United States of America.
authors.forename: Xin
authors.initials: X
authors.lastname: Yao
authors.affiliation: Department of Biology, Xavier University of Louisiana, New Orleans, Louisiana, United States of America.
authors.forename: Scott
authors.initials: S
authors.lastname: Jennings
authors.affiliation: Department of Biology, Xavier University of Louisiana, New Orleans, Louisiana, United States of America.
authors.forename: Shubha Kale
authors.initials: SK
authors.lastname: Ireland
authors.affiliation: Department of Biology, Xavier University of Louisiana, New Orleans, Louisiana, United States of America.
authors.forename: Tri
authors.initials: T
authors.lastname: Pham
authors.affiliation: Department of Biology, Xavier University of Louisiana, New Orleans, Louisiana, United States of America.
authors.forename: Brandi
authors.initials: B
authors.lastname: Temple
authors.affiliation: Department of Biology, Xavier University of Louisiana, New Orleans, Louisiana, United States of America.
authors.forename: Mya
authors.initials: M
authors.lastname: Davis
authors.affiliation: Center for Nanomedicine, Sanford-Burnham Medical Research Institute, University of California Santa Barbara, Santa Barbara, California, United States of America; Department of Molecular, Cell and Developmental Biology, University of California Santa Barbara, Santa Barbara, California, United States of America.
authors.forename: Renwei
authors.initials: R
authors.lastname: Chen
authors.affiliation: Department of Biology, Xavier University of Louisiana, New Orleans, Louisiana, United States of America.
authors.forename: Ian
authors.initials: I
authors.lastname: Davenport
authors.affiliation: Department of Biology, Xavier University of Louisiana, New Orleans, Louisiana, United States of America.
authors.forename: Hector
authors.initials: H
authors.lastname: Biliran
mesh_terms: D000818:Animals; D023102:Anoikis / Q000235:genetics*; D002265:Carboxylic Ester Hydrolases / Q000235:genetics* / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D056970:Co-Repressor Proteins; D004195:Disease Models, Animal; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000235:genetics* / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism; D047368:Tumor Burden; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D056970:Co-Repressor Proteins; D024101:Mitochondrial Proteins; D012097:Repressor Proteins; C499043:TLE1 protein, human; C498445:TLE5 protein, human; D025521:Tumor Suppressor Proteins; D002265:Carboxylic Ester Hydrolases; C483418:PTH2 protein, human; D020169:Caspases