Novel light delivery method for performing transbronchial photodynamic therapy ablation to treat peripheral lung cancer: A pilot study.

BACKGROUND: Photodynamic therapy involves using a photosensitizer with l illumination and is recommended for treating early, centrally located lung cancers, but it is not a standard treatment for peripheral lung tumor.. We previously proposed a novel light delivery method, in which lipiodol is perfused into the bronchial tree to increase the scope of illumination via the fiber effect. Herein, we attempted this novel technique under electromagnetic bronchoscope guidance in a hybrid operation room where lipiodol facilitated light diffusion, and evaluated the effectiveness and feasibility of this technique for peripheral lung cancers. METHODS: This phase 0 pilot study included three patients with peripheral lung cancers (primary tumors ≤20-mm diameter). The photodynamic therapy was administered using Porfimer sodium as the photosensitizer, and an electromagnetic navigation bronchoscope in a hybrid operating room to guide the catheter to the tumor. This facilitated lipiodol infusion to encase the tumor and permit the transbronchial photodynamic therapy ablation. RESULTS: Administering 630 nm 200 J/cm (400mW/500sec) energy through a 3-cm cylindrical diffusing laser fiber was safe; no significant acute complications were observed. Although the treatment outcome was unsatisfactory due to the low light dose, tumor pathology in one case revealed tumor necrosis, with no significant damage to the surrounding lung tissue. CONCLUSIONS: Novel light delivery transbronchial photodynamic therapy ablation for peripheral lung tumors is feasible and safe. Additional clinical trials may help determine the best illumination plan and light dose through multiple deliveries from multiple angles.

Propolin G-Suppressed Epithelial-to-Mesenchymal Transition in Triple-Negative Breast Cancer Cells via Glycogen Synthase Kinase 3ß-Mediated Snail and HDAC6-Regulated Vimentin Degradation.

Triple-negative breast cancer (TNBC) is a highly aggressive breast cancer with a poor prognosis. The incidence and mortality rate of TNBC are frequently found in younger women. Due to the absence of a good therapeutic strategy, effective remedies for inhibiting TNBC have been developed for improving the cure rate. Epithelial-to-mesenchymal transition (EMT) is a critical mechanism to regulate cancer cell motility and invasion. Furthermore, ectopic expression of EMT molecules correlates with the metastasis and poor prognosis of TNBC. Targeting EMT might be a strategy for the therapy and prevention of TNBC. Propolin G, an active c-prenylflavanone in Taiwanese propolis, has been shown to possess anti-cancer activity in many cancers. However, the anti-metastasis activity of propolin G on TNBC is still unclear. The present study showed that the migration and invasion activities of TNBC cells was suppressed by propolin G. Down-regulated expression of Snail and vimentin and up-regulated expression of E-cadherin were dose- and time-dependently observed in propolin G-treated MDA-MB-231 cells. Propolin G inhibited Snail and vimentin expressions via the signaling pathways associated with post-translational modification. The activation of glycogen synthase kinase 3ß (GSK-3ß) by propolin G resulted in increasing GSK-3ß interaction with Snail. Consequently, the nuclear localization and stability of Snail was disrupted resulting in promoting the degradation. Propolin G-inhibited Snail expression and the activities of migration and invasion were reversed by GSK-3ß inhibitor pretreatment. Meanwhile, the outcomes also revealed that histone deacetylase 6 (HDAC6) activity was dose-dependently suppressed by propolin G. Correspondently, the amounts of acetyl-α-tubulin, a down-stream substrate of HDAC6, were increased. Dissociation of HDAC6/Hsp90 with vimentin leading to increased vimentin acetylation and degradation was perceived in the cells with the addition of propolin G. Moreover, up-regulated expression of acetyl-α-tubulin by propolin G was attenuated by HDAC6 overexpression. On the contrary, down-regulated expression of vimentin, cell migration and invasion by propolin G were overturned by HDAC6 overexpression. Conclusively, restraint cell migration and invasion of TNBC by propolin G were activated by the expression of GSK-3ß-suppressed Snail and the interruption of HDAC6-mediated vimentin protein stability. Aiming at EMT, propolin G might be a potential candidate for TNBC therapy.

Induction of G2/M Cell Cycle Arrest via p38/p21Waf1/Cip1-Dependent Signaling Pathway Activation by Bavachinin in Non-Small-Cell Lung Cancer Cells.

Lung cancer is the most commonly diagnosed malignant cancer in the world. Non-small-cell lung cancer (NSCLC) is the major category of lung cancer. Although effective therapies have been administered, for improving the NSCLC patient's survival, the incident rate is still high. Therefore, searching for a good strategy for preventing NSCLC is urgent. Traditional Chinese medicine (TCM) are brilliant materials for cancer chemoprevention, because of their high biological safety and low cost. Bavachinin, which is an active flavanone of Proralea corylifolia L., possesses anti-inflammation, anti-angiogenesis, and anti-cancer activities. The present study's aim was to evaluate the anti-cancer activity of bavachinin on NSCLC, and its regulating molecular mechanisms. The results exhibited that a dose-dependent decrease in the cell viability and colony formation capacity of three NSCLC cell lines, by bavachinin, were through G2/M cell cycle arrest induction. Meanwhile, the expression of the G2/M cell cycle regulators, such as cyclin B, p-cdc2Y15, p-cdc2T161, and p-wee1, was suppressed. With the dramatic up-regulation of the cyclin-dependent kinase inhibitor, p21Waf1/Cip1, the expression and association of p21Waf1/Cip1 with the cyclin B/cdc2 complex was observed. Silencing the p21Waf1/Cip1 expression significantly rescued bavachinin-induced G2/M cell accumulation. Furthermore, the expression of p21Waf1/Cip1 mRNA was up-regulated in bavachinin-treated NSCLC cells. In addition, MAPK and AKT signaling were activated in bavachinin-added NSCLC cells. Interestingly, bavachinin-induced p21Waf1/Cip1 expression was repressed after restraint p38 MAPK activation. The inhibition of p38 MAPK activation reversed bavachinin-induced p21Waf1/Cip1 mRNA expression and G2/M cell cycle arrest. Collectively, bavachinin-induced G2/M cell cycle arrest was through the p38 MAPK-mediated p21Waf1/Cip1-dependent signaling pathway in the NSCLC cells.

Suppressing migration and invasion of H1299 lung cancer cells by honokiol through disrupting expression of an HDAC6-mediated matrix metalloproteinase 9.

Metastasis is the crucial mechanism to cause high mortality in lung cancer. Degradation of extracellular matrix (ECM) by proteolytic enzymes, especially matrix metalloproteinases (MMPs), is a key process for promoting cancer cell migration and invasion. Therefore, targeting MMPs might be a strategy for lung cancer metastasis suppression. Honokiol, a biological active component of Magnolia officinalis, has been indicated to suppress lung cancer tumorigenesis through epigenetic regulation. However, the regulation of MMPs-mediated migration and invasion by honokiol through epigenetic regulation in lung cancer is still a mystery. In the present study, the migration and invasion ability of H1299 lung cancer was suppressed by noncytotoxic concentrations of honokiol treatment. The proteolytic activity of MMP-9, rather than MMP-2, was inhibited in honokiol-treated H1299 cells. Honokiol-inhibited MMP-9 expression was through promoting MMP-9 protein degradation rather than suppressing transcription mechanism. Furthermore, the expression of specific histone deacetylases 6 (HDAC6) substrate, acetyl-α-tubulin, was accumulated after honokiol incubation. The disassociation of MMP-9 with hyper-acetylated heat shock protein 90 (Hsp90) was observed resulting in MMP-9 degradation after honokiol treatment. Meanwhile, honokiol-suppressed MMP-9 expression and invasion ability of H1299 lung cancer cells was rescued by HDAC6 overexpression. Accordingly, the results suggested that the suppression of migration and invasion activities by honokiol was through inhibiting HDAC6-mediated Hsp90/MMP-9 interaction and followed by MMP-9 degradation in lung cancer.

Propolin C Inhibited Migration and Invasion via Suppression of EGFR-Mediated Epithelial-to-Mesenchymal Transition in Human Lung Cancer Cells.

Controlling lung cancer cell migration and invasion via epithelial-to-mesenchymal transition (EMT) through the regulation of epidermal growth factor receptor (EGFR) signaling pathway has been demonstrated. Searching biological active phytochemicals to repress EGFR-regulated EMT might prevent lung cancer progression. Propolis has been used as folk medicine in many countries and possesses anti-inflammatory, antioxidant, and anticancer activities. In this study, the antimigration and anti-invasion activities of propolin C, a c-prenylflavanone from Taiwanese propolis, were investigated on EGFR-regulated EMT signaling pathway. Cell migration and invasion activities were dose-dependently suppressed by noncytotoxic concentration of propolin C. Downregulations of vimentin and snail as well as upregulation of E-cadherin expressions were through the inhibition of EGFR-mediated phosphatidylinositol-3-kinase/protein kinase B (PI3K/Akt) and extracellular signal-regulated kinase (ERK) signaling pathway in propolin C-treated cells. In addition, EGF-induced migration and invasion were suppressed by propolin C-treated A549 lung cancer cells. No significant differences in E-cadherin expression were observed in EGF-stimulated cells. Interestingly, EGF-induced expressions of vimentin, snail, and slug were suppressed through the inhibition of PI3K/Akt and ERK signaling pathway in propolin C-treated cells. Inhibition of cell migration and invasion by propolin C was through the inhibition of EGF/EGFR-mediated signaling pathway, followed by EMT suppression in lung cancer.

Shikonin Inhibited Migration and Invasion of Human Lung Cancer Cells via Suppression of c-Met-Mediated Epithelial-to-Mesenchymal Transition.

Epithelial-to-mesenchymal transition (EMT) is a major process to regulate cell migration and invasion. Inhibition of epidermal growth factor receptor (EGFR)-mediated EMT by tyrosine kinase inhibitors (TKIs) is a strategy to prevent lung cancer invasion. However, drug resistance is emerged and accelerated invasion through other signaling bypassing EGFR after TKIs therapy. c-Met signaling pathway is highly activated in EGFR-mutated lung cancer cells. Targeting c-Met signaling pathway may be a strategy to suppress EGFR-independent migration and invasion for lung cancer therapy. Therefore, we examined the anti-migration and anti-invasion abilities of shikonin, an active compound from Lithospermum erythrorhizon, in highly and ligand-induced c-Met activation lung cancer cells. Our results revealed that cell viability and cell cycle progression did not change under 1 µM of shikoinin treatment in highly c-Met expressive HCC827 lung cancer cells. Endogenous c-Met activation was dose-dependently inhibited and the migration and invasion activity of HCC827 cells were suppressed by shikonin treatment. Induction of E-cadherin expression and inhibition of vimentin, slug, and snail expression by shikonin was through c-Met-mediated PI3K/Akt and ERK signaling suppression. Furthermore, hepatocyte growth factor (HGF)-induced migration, invasion and EMT marker change were reversed by shikonin in low c-Met expressive A549 lung cancer cells. Inhibition of HGF-induced c-Met, PI3K/Akt and MEK/ERK activation were observed in shikonin-treated cells. Co-treatment of PI3K/Akt inhibitor or ERK inhibitor with shikonin enhanced shikonin-reversed HGF-regulated EMT marker expression. Taken together, the results suggested that the anti-migration and anti-invasion activities of shikonin was through c-Met inhibition and following by EMT suppression in lung cancer. J. Cell. Biochem. 118: 4639-4651, 2017. © 2017 Wiley Periodicals, Inc.

Emergency visits among end-of-life cancer patients in Taiwan: a nationwide population-based study.

BACKGROUND: An increased number of emergency visits at the end of life may indicate poor-quality cancer care. The study aimed to investigate the prevalence and utilization of emergency visits and to explore the reasons for emergency department (ED) visits among cancer patients at the end of life. METHODS: A retrospective cohort study was performed by tracking one year of ambulatory medical service records before death. Data were collected from the cancer dataset of Taiwan's National Health Insurance Research Database (NHIRD). RESULTS: A total of 32,772 (19.2%) patients with malignant cancer visited EDs, and 23,883 patients died during the study period. Of these, the prevalence of emergency visits in the mortality group was 81.5%, and their ED utilization was significantly increased monthly to the end of life. The most frequent types of cancer were digestive and peritoneum cancers (34.8%), followed by breast cancer (17.7%) and head and neck cancers (13.3%). Older patients, males, and those diagnosed with metastases, respiratory or digestive cancer were more likely to use ED services at the end of life. Use of an ED service in the nearest community hospital to replace medical centers for dying cancer patients would be more acceptable in emergency situations. CONCLUSIONS: Our study provided population-based evidence related to ED utilization. An understanding of the reasons for such visits could be useful in preventing overuse of ED visits to improve the quality of end-of-life care.

NBM-T-BBX-OS01, Semisynthesized from Osthole, Induced G1 Growth Arrest through HDAC6 Inhibition in Lung Cancer Cells.

Disrupting lung tumor growth via histone deacetylases (HDACs) inhibition is a strategy for cancer therapy or prevention. Targeting HDAC6 may disturb the maturation of heat shock protein 90 (Hsp90) mediated cell cycle regulation. In this study, we demonstrated the effects of semisynthesized NBM-T-BBX-OS01 (TBBX) from osthole on HDAC6-mediated growth arrest in lung cancer cells. The results exhibited that the anti-proliferative activity of TBBX in numerous lung cancer cells was more potent than suberoylanilide hydroxamic acid (SAHA), a clinically approved pan-HDAC inhibitor, and the growth inhibitory effect has been mediated through G1 growth arrest. Furthermore, the protein levels of cyclin D1, CDK2 and CDK4 were reduced while cyclin E and CDK inhibitor, p21Waf1/Cip1, were up-regulated in TBBX-treated H1299 cells. The results also displayed that TBBX inhibited HDAC6 activity via down-regulation HDAC6 protein expression. TBBX induced Hsp90 hyper-acetylation and led to the disruption of cyclin D1/Hsp90 and CDK4/Hsp90 association following the degradation of cyclin D1 and CDK4 proteins through proteasome. Ectopic expression of HDAC6 rescued TBBX-induced G1 arrest in H1299 cells. Conclusively, the data suggested that TBBX induced G1 growth arrest may mediate HDAC6-caused Hsp90 hyper-acetylation and consequently increased the degradation of cyclin D1 and CDK4.

Leukocytosis in polycythemia vera and splenomegaly in essential thrombocythemia are independent risk factors for hemorrhage.

BACKGROUND: Long-term outcomes are favorable for patients with polycythemia vera (PV) and for patients with essential thrombocythemia (ET). However, hemorrhage is a significant cause of morbidity and mortality in those patients. METHODS: We retrospectively recruited 247 patients who had received a diagnosis of PV (n = 101) or ET (n = 146) during the period 2001-2010. RESULTS: After a median follow-up period of 36.2 months, the cumulative incidence of hemorrhage was 39.6% in patients with PV (6.2% per person-year) and 29.7% in patients with ET (5.9% person-years). Episodes of major bleeding occurred in 9.9% of patients with PV and in 14.4% of patients with ET. Overall survival was significantly shorter among patients with hemorrhage than among those without said complication (P < 0.001 for overall patients; P = 0.002 for patients with PV; P = 0.026 for patients with ET). In the univariate analysis, age ≥ 60 yr (OR: 4.77, P = 0.046) and WBC ≥ 16 × 10(9) /L (OR: 4.15, P = 0.010) were predictors of hemorrhage in patients with PV, and age ≥ 60 yr (OR: 3.25, P = 0.040), WBC ≥ 16 × 10(9) /L (OR: 2.89, P = 0.024), albumin <4.0 g/dL (OR: 4.10, P = 0.002), and splenomegaly (OR: 5.19, P = 0.002) were predictors of hemorrhage in patients with ET. Multivariate analysis showed that WBC ≥ 16 × 10(9) /L was the only significant risk factor for hemorrhage in patients with PV (OR: 3.51, P = 0.026) and that splenomegaly was the only risk factor for hemorrhage in patients with ET (OR: 3.00, P = 0.048). CONCLUSION: Leukocytosis in PV and splenomegaly in ET are independent risk factors for hemorrhage.

Comparison of surgical resection and transarterial chemoembolization for hepatocellular carcinoma beyond the Milan criteria: a propensity score analysis.

BACKGROUND: Treatment for patients with intermediate-stage hepatocellular carcinoma (HCC) is controversial. This study compared the long-term survival of patients beyond the Milan criteria who received surgical resection (SR) or transarterial chemoembolization (TACE). METHODS: A total of 268 and 455 HCC patients beyond the Milan criteria undergoing SR and TACE, respectively, were retrospectively evaluated. After propensity score analysis to adjust for baseline differences, 146 pairs of matched patients were selected from each treatment arm. Long-term survival was compared by the Kaplan-Meier method. Independent prognostic predictors were determined by the Cox proportional hazards model. RESULTS: Long-term survival was significantly better for the SR group by univariate survival analysis (P < .001). In the Cox model, SR was identified as an independent predictor of better prognosis (hazard ratio = 0.3, 95% confidence interval [95% CI]: 0.23-0.4; P < .001). Despite similar baseline characteristics in the propensity score model, patients who underwent SR had significantly better survival than patients who underwent TACE (P < .001). Patients receiving TACE had 2.56-fold increased risk of long-term mortality in the propensity model (95% CI: 1.73-3.78). The SR and TACE groups had comparable 30- and 90-day posttreatment mortality. The Cox model consistently disclosed the significant superiority of SR in terms of long-term survival in the propensity score model (P < .001). CONCLUSIONS: For HCC patients beyond the Milan criteria, SR is considered equally safe as TACE and provides better long-term survival. SR may be regarded as the priority treatment for these patients.

Chronic hepatitis virus infection in patients with multiple myeloma: clinical characteristics and outcomes.

OBJECTIVES: Cytotoxic agents and steroids are used to treat lymphoid malignancies, but these compounds may exacerbate chronic viral hepatitis. For patients with multiple myeloma, the impact of preexisting hepatitis virus infection is unclear. The aim of this study is to explore the characteristics and outcomes of myeloma patients with chronic hepatitis virus infection. METHODS: From 2003 to 2008, 155 myeloma patients were examined to determine their chronic hepatitis virus infection statuses using serologic tests for the hepatitis B (HBV) and C viruses (HCV). Clinical parameters and outcome variables were retrieved via a medical chart review. RESULTS: The estimated prevalences of chronic HBV and HCV infections were 11.0% (n = 17) and 9.0% (n = 14), respectively. The characteristics of patients who were hepatitis virus carriers and those who were not were similar. However, carrier patients had a higher prevalence of conventional cytogenetic abnormalities (64.3% vs. 25.0%). The cumulative incidences of grade 3-4 elevation of the level of alanine transaminase, 30.0% vs. 12.0%, and hyperbilirubinemia, 20.0% vs. 1.6%, were higher in carriers as well. In a Kaplan-Meier analysis, carrier patients had worse overall survival (median: 16.0 vs. 42.4 months). The prognostic value of carrier status was not statistically significant in the multivariate analysis, but an age of more than 65 years old, the presence of cytogenetic abnormalities, a beta-2-microglobulin level of more than 3.5 mg/L, and a serum creatinine level of more than 2 mg/ dL were independent factors associated with poor prognosis. CONCLUSION: Myeloma patients with chronic hepatitis virus infections might be a distinct subgroup, and close monitoring of hepatic adverse events should be mandatory.

Low absolute lymphocyte count and addition of rituximab confer high risk for interstitial pneumonia in patients with diffuse large B-cell lymphoma.

Several small-scale studies have reported pulmonary toxicity among patients with diffuse large B-cell lymphoma (DLBCL) receiving rituximab-containing chemotherapy, though whether the use of rituximab predisposes to interstitial pneumonia (IP) remains unclear. This retrospective study was intended to identify the characteristics and risk factors of IP in patients with DLBCL. Between 2000 and 2009, 529 consecutive patients with DLBCL receiving first-line tri-weekly COP- or CHOP-based chemotherapy with or without rituximab were enrolled as subjects. IP was defined as diffuse pulmonary interstitial infiltrates found on computed tomography scans in conjunction with respiratory symptoms. IP was observed in 26 patients (4.9%), six of whom were confirmed with Pneumocystis jirovecii pneumonia. The median number of chemotherapy courses before IP was four cycles. Using multivariate analysis, absolute lymphocyte count less than 1×10(9)/l at diagnosis [odds ratio (OR) 2.75, p=0.014] and the addition of rituximab to chemotherapy (OR 4.56, p=0.003) were identified as independent risk factors for IP. In conclusion, the incidence of IP is increased in patients with DLBCL receiving rituximab-containing chemotherapy. Specific subgroups with lymphopenia at diagnosis may justify close scrutiny to detect pulmonary complications.

Chronic hepatitis virus infection in patients with multiple myeloma: clinical characteristics and outcomes

OBJECTIVES: Cytotoxic agents and steroids are used to treat lymphoid malignancies, but these compounds may exacerbate chronic viral hepatitis. For patients with multiple myeloma, the impact of preexisting hepatitis virus infection is unclear. The aim of this study is to explore the characteristics and outcomes of myeloma patients with chronic hepatitis virus infection. METHODS: From 2003 to 2008, 155 myeloma patients were examined to determine their chronic hepatitis virus infection statuses using serologic tests for the hepatitis B (HBV) and C viruses (HCV). Clinical parameters and outcome variables were retrieved via a medical chart review. RESULTS: The estimated prevalences of chronic HBV and HCV infections were 11.0 percent (n = 17) and 9.0 percent (n = 14), respectively. The characteristics of patients who were hepatitis virus carriers and those who were not were similar. However, carrier patients had a higher prevalence of conventional cytogenetic abnormalities (64.3 percent vs. 25.0 percent). The cumulative incidences of grade 3-4 elevation of the level of alanine transaminase, 30.0 percent vs. 12.0 percent, and hyperbilirubinemia, 20.0 percent vs. 1.6 percent, were higher in carriers as well. In a Kaplan-Meier analysis, carrier patients had worse overall survival (median: 16.0 vs. 42.4 months). The prognostic value of carrier status was not statistically significant in the multivariate analysis, but an age of more than 65 years old, the presence of cytogenetic abnormalities, a beta-2-microglobulin level of more than 3.5 mg/L, and a serum creatinine level of more than 2 mg/ dL were independent factors associated with poor prognosis. CONCLUSION: Myeloma patients with chronic hepatitis virus infections might be a distinct subgroup, and close monitoring of hepatic adverse events should be mandatory.

Clinical features and prognostic factors of angioimmunoblastic T-cell lymphoma in Taiwan: a single-institution experience.

Angioimmunoblastic T-cell lymphoma (AITL) is a rare subtype of peripheral T-cell lymphoma that carries a poor prognosis. This study retrospectively analyzed patients with AITL from a single institution in Taiwan, aiming to define the clinical features and prognostic factors. Patients with AITL treated at our institution from February 1988 through January 2010 were enrolled. Factors associated with overall survival (OS) were determined by statistical methods. A total of 31 Taiwanese patients (21 males) were identified. The median age was 74 years (range, 27-90). Among all patients, 67.7% were Ann Arbor stage III or IV, 58.1% presented with B symptoms, 48.4% had hypoalbuminenia (<35 g/L), and 63.3% had elevated lactate dehydrogenase (LDH) at diagnosis. First-line chemotherapy was mostly CHOP (cyclophosphamide, vincristine, doxorubicin, and prednisolone)-based and complete response (CR) was achieved in 25% of patients. The actuarial 2-year survival rate was 38.7%, and the median OS was 14.9 months. In multivariate analysis, initial presentation with fever (p = 0.035), advanced stage (p = 0.024), and failure to achieve CR (p = 0.029) were independent adverse factors associated with poorer OS. Interestingly, OS did not differ whether chemotherapy regimens contained anthracycline or not. Taiwanese patients with AITL were usually elderly. Despite the prognosis being generally poor, patients with AITL should be treated with the goal of achieving CR, regardless of anthracycline- or non-anthracycline-based chemotherapy.

Identification of endothelial genes up-regulated in vivo.

We have used microarrays to identify genes that are selectively expressed in endothelial cells in vivo. Analysis of freshly isolated endothelial cells from the lungs and kidneys reveals that 350 out of the 10,000 genes represented on the microarrays were expressed at higher levels than by the corresponding parenchymal cells. Thirteen of these genes were identified both in the lung and kidney screens from a subset of about 5000 genes. Many of these genes are known to be specifically expressed in endothelial cells, but about 200 genes were potentially novel endothelial genes. The preferential endothelial expression of a selected group of these genes was confirmed by quantitative polymerase chain reaction or in situ mRNA hybridization. Comparison of the genes expressed in lung and kidney endothelia revealed numerous differences. Notably, genes encoding components of an ephrin signaling pathway were highly expressed in lung endothelial cells. In summary, the genes we have identified represent potentially new pan-endothelial and tissue-specific endothelial markers.

A mitochondrial protein, Bit1, mediates apoptosis regulated by integrins and Groucho/TLE corepressors.

A delicate balance of signals regulates cell survival. One set of these signals is derived from integrin-mediated cell adhesion to the extracellular matrix (ECM). Loss of cell attachment to the ECM causes apoptosis, a process known as anoikis. In searching for proteins involved in cell adhesion-dependent regulation of anoikis, we identified Bit1, a mitochondrial protein that is released into the cytoplasm during apoptosis. Cytoplasmic Bit1 forms a complex with AES, a small Groucho/transducin-like enhancer of split (TLE) protein, and induces cell death with characteristics of caspase-independent apoptosis. Cell attachment to fibronectin counteracts the apoptotic effect of Bit1 and AES. Increasing Bit1 expression enhances anoikis, while suppressing the expression reduces it. Thus, we have elucidated an integrin-controlled pathway that is, at least in part, responsible for the cell survival effects of cell-ECM interactions.