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Aaron D. Schimmer – One of the best experts on this subject based on the ideXlab platform.

  • A genome wide shRNA screen identifies α/β hydrolase domain containing 4 (ABHD4) as a novel regulator of Anoikis resistance
    Apoptosis, 2012
    Co-Authors: Craig D. Simpson, Rose Hurren, Dahlia Kasimer, Neil Maclean, Yanina Eberhard, Troy Ketela, Jason Moffat, Aaron D. Schimmer

    Abstract:

    Acquisition of resistance to anchorage dependant cell death, a process termed Anoikis, is a requirement for cancer cell metastasis. However, the molecular determinants of Anoikis resistance and sensitivity are poorly understood. To better understand resistance to Anoikis we conducted a genome wide lentiviral shRNA screen to identify genes whose knockdown render Anoikis-sensitive RWPE-1 prostate cells resistant to Anoikis. RWPE-1 cells were infected with a pooled lentiviral shRNA library with 54,021 shRNA targeting 11,255 genes. After infection, an Anoikis-resistant cell population was selected and shRNA sequences were amplified and sequenced. Thirty-four shRNA sequences reproducibly protected RWPE-1 cells from Anoikis after culture under suspension conditions including the top validated hit, α/β hydrolase domain containing 4 (ABHD4). In validation studies, ABHD4 knockdown inhibited Anoikis in RWPE-1 cells as well as Anoikis sensitive NP69 nasopharyngeal and OVCAR3 ovarian cancer cells, while over-expression of the gene increased sensitivity. Induction of Anoikis after ABHD4 knockdown was associated with cleavage of PARP and activation of caspases-3, but was independent in changes of FLIP, FAK and Src expression. Interestingly, induction of Anoikis after ABHD4 knockdown was independent of the known role of ABHD4 in the anandamide synthesis pathway and the generation of glycerophospho- N -acyl ethanolamines. Thus, ABHD4 is a novel genetic regulator of Anoikis sensitivity.

  • Anoikis resistance and tumor metastasis
    Cancer Letters, 2008
    Co-Authors: Craig D. Simpson, Kika Anyiwe, Aaron D. Schimmer

    Abstract:

    As a barrier to metastases, cells normally undergo apoptosis after they lose contact with their extra cellular matrix or their neighbouring cells. This cell death process has been termed “Anoikis“. Tumour cells that acquire malignant potential have developed mechanisms to resist Anoikis and thereby survive after detachment from their primary site and while travelling through the lymphatic and circulatory systems. Defects in the death receptor pathway of caspase activation, such as the over-expression of the caspase-8 inhibitor FLIP, can render cells resistant to Anoikis. Likewise, roadblocks in the mitochondrial pathway, such as over-expression of the Bcl-2 family of anti-apoptotic proteins, can also confer resistance to Anoikis. This review will focus on the roles of the death receptor and mitochondrial pathways in Anoikis and Anoikis resistance and how targeting defects in these pathways can restore sensitivity to Anoikis and serve as the basis for therapeutic adjuncts that prevent metastasis.

  • A chemical screen identifies anisomycin as an Anoikis sensitizer that functions by decreasing FLIP protein synthesis.
    Cancer Research, 2007
    Co-Authors: Imtiaz A. Mawji, Craig D. Simpson, Marcela Gronda, Moyo A. Williams, Rose Hurren, Clare Henderson, Alessandro Datti, Jeffrey L. Wrana, Aaron D. Schimmer

    Abstract:

    Malignant epithelial cells with metastatic potential resist apoptosis that normally occurs upon loss of anchorage from the extracellular matrix, a process termed “Anoikis.” Resistance to Anoikis enables malignant cells to survive in an anchorage-independent manner, which leads to the formation of distant metastases. To understand the regulation of Anoikis, we designed, automated, and conducted a high-throughput chemical screen for Anoikis sensitizers. PPC-1 Anoikis–resistant prostate cancer cells were seeded in hydrogel-coated ultralow binding plates for suspension conditions and standard tissue culture plates to promote adhesion. After seeding, cells were treated with aliquots from a library of previously characterized small molecules, and viability was assessed using the 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt, assay. From this chemical screen, we identified anisomycin that induced apoptosis in suspension conditions, but was not toxic to these cells grown under adherent conditions. Anisomycin sensitized cells to Anoikis by decreasing levels of the caspase-8 inhibitor FLIP and subsequently activating the death receptor pathway of caspase activation. Although anisomycin activated c-Jun-NH2-kinase and p38, these kinases were not functionally important for the effect of anisomycin on Anoikis and FLIP. Rather, anisomycin decreased FLIP and sensitized cells to Anoikis by inhibiting its protein synthesis. Finally, we showed that anisomycin decreased distal tumor formation in a mouse model of prostate cancer metastases. Thus, a novel chemical screen identified anisomycin as an Anoikis sensitizer that acts by decreasing FLIP protein synthesis. Our results suggest that FLIP is a suppressor of Anoikis and inhibiting FLIP protein synthesis may be a useful antimetastatic strategy. [Cancer Res 2007;67(17):8307–15]

Craig D. Simpson – One of the best experts on this subject based on the ideXlab platform.

  • A genome wide shRNA screen identifies α/β hydrolase domain containing 4 (ABHD4) as a novel regulator of Anoikis resistance
    Apoptosis, 2012
    Co-Authors: Craig D. Simpson, Rose Hurren, Dahlia Kasimer, Neil Maclean, Yanina Eberhard, Troy Ketela, Jason Moffat, Aaron D. Schimmer

    Abstract:

    Acquisition of resistance to anchorage dependant cell death, a process termed Anoikis, is a requirement for cancer cell metastasis. However, the molecular determinants of Anoikis resistance and sensitivity are poorly understood. To better understand resistance to Anoikis we conducted a genome wide lentiviral shRNA screen to identify genes whose knockdown render Anoikis-sensitive RWPE-1 prostate cells resistant to Anoikis. RWPE-1 cells were infected with a pooled lentiviral shRNA library with 54,021 shRNA targeting 11,255 genes. After infection, an Anoikis-resistant cell population was selected and shRNA sequences were amplified and sequenced. Thirty-four shRNA sequences reproducibly protected RWPE-1 cells from Anoikis after culture under suspension conditions including the top validated hit, α/β hydrolase domain containing 4 (ABHD4). In validation studies, ABHD4 knockdown inhibited Anoikis in RWPE-1 cells as well as Anoikis sensitive NP69 nasopharyngeal and OVCAR3 ovarian cancer cells, while over-expression of the gene increased sensitivity. Induction of Anoikis after ABHD4 knockdown was associated with cleavage of PARP and activation of caspases-3, but was independent in changes of FLIP, FAK and Src expression. Interestingly, induction of Anoikis after ABHD4 knockdown was independent of the known role of ABHD4 in the anandamide synthesis pathway and the generation of glycerophospho- N -acyl ethanolamines. Thus, ABHD4 is a novel genetic regulator of Anoikis sensitivity.

  • inhibition of the sodium potassium adenosine triphosphatase pump sensitizes cancer cells to Anoikis and prevents distant tumor formation
    Cancer Research, 2009
    Co-Authors: Craig D. Simpson, Kika Anyiwe, Imtiaz A. Mawji, Marcela Gronda, Moyo A. Williams, Rose Hurren, Xiaoming Wang, Amudha Venugopal, Sonia Cheng, Stefano Serra

    Abstract:

    Normal epithelial cells undergo apoptosis upon detachment from the extracellular matrix, a process termed “Anoikis.” However, malignant epithelial cells with metastatic potential resist Anoikis and can survive in an anchorage-independent fashion. Molecules that sensitize resistant cells to Anoikis will be useful chemical probes to understand this pathway. To identify novel Anoikis sensitizers in Anoikis-resistant PPC-1 prostate adenocarcinoma cells, a library of 2,000 off-patent drugs and natural products was screened for their ability to preferentially induce cell death in suspension over adherent culture conditions. This screen identified five members of the family of cardiac glycosides as Anoikis sensitizers, including ouabain, peruvoside, digoxin, digitoxin, and strophanthidin. We conducted further studies with ouabain to discern the mechanism of cardiac glycoside-induced Anoikis sensitization. Ouabain initiated Anoikis through the mitochondrial pathway of caspase activation. In addition, ouabain sensitized cells to Anoikis by inhibiting its known target, the Na(+)/K(+) ATPase pump, and inducing hypoosmotic stress. Resistance to Anoikis permits cancer cells to survive in the circulation and facilitates their metastasis to distant organs, so we tested the effects of Na(+)/K(+) ATPase inhibition on distant tumor formation in mouse models. In these mouse models, ouabain inhibited tumor metastases but did not alter the growth of subcutaneous tumors. Thus, we have identified a novel mechanism to sensitize resistant cells to Anoikis and decrease tumor metastasis. These results suggest a potential mechanism for the observed clinical reduction in metastasis and relapse in breast cancer patients who have undergone treatments with cardiac glycosides.

  • Anoikis resistance and tumor metastasis
    Cancer Letters, 2008
    Co-Authors: Craig D. Simpson, Kika Anyiwe, Aaron D. Schimmer

    Abstract:

    As a barrier to metastases, cells normally undergo apoptosis after they lose contact with their extra cellular matrix or their neighbouring cells. This cell death process has been termed “Anoikis“. Tumour cells that acquire malignant potential have developed mechanisms to resist Anoikis and thereby survive after detachment from their primary site and while travelling through the lymphatic and circulatory systems. Defects in the death receptor pathway of caspase activation, such as the over-expression of the caspase-8 inhibitor FLIP, can render cells resistant to Anoikis. Likewise, roadblocks in the mitochondrial pathway, such as over-expression of the Bcl-2 family of anti-apoptotic proteins, can also confer resistance to Anoikis. This review will focus on the roles of the death receptor and mitochondrial pathways in Anoikis and Anoikis resistance and how targeting defects in these pathways can restore sensitivity to Anoikis and serve as the basis for therapeutic adjuncts that prevent metastasis.

Sanjay K. Srivastava – One of the best experts on this subject based on the ideXlab platform.

  • HER2-mediated GLI2 stabilization promotes Anoikis resistance and metastasis of breast cancer cells.
    Cancer letters, 2018
    Co-Authors: Parul Gupta, Neel M. Fofaria, Nehal Gupta, Alok Ranjan, Sanjay K. Srivastava

    Abstract:

    Breast cancer metastasis is a multi-step process and requires cells to overcome Anoikis. Anoikis is defined as cell-death that occurs due to loss of cell adhesion. During the course of cancer progression, tumor cells acquire resistance to Anoikis. However, mechanisms of Anoikis resistance are not clear. Human epidermal growth receptor 2 (HER2) overexpressing breast tumors are known to be highly aggressive and metastatic. The mechanisms correlating HER2 with metastasis are poorly understood. We observed increased Anoikis resistance in HER2 overexpressing breast cancer cells. In addition, we identified that HER2 overexpression was also associated with increased sonic hedgehog (SHH) signaling especially GLI2, and that inhibition of SHH pathway suppressed Anoikis resistance. GSK3β is known to facilitate proteasome-mediated degradation of GLI2. Moreover, we observed that silencing of GLI2 resulted in reduced migration and invasion of HER2 overexpressing cells. Anoikis resistant HER2 overexpressing cells also showed increased rate and extent of metastasis in vivo, as compared to wild type Anoikis resistant cells. Taken together, this study indicates a novel role of HER2/GSK3β/GLI2 axis in Anoikis resistance and metastasis, and that GLI2 could be a potential target for anti-cancer therapies.

  • STAT3 induces Anoikis resistance, promotes cell invasion and metastatic potential in pancreatic cancer cells.
    Carcinogenesis, 2014
    Co-Authors: Neel M. Fofaria, Sanjay K. Srivastava

    Abstract:

    Tumor cells need to attain Anoikis resistance to survive prior to metastasis making it a vital trait of malignancy. The mechanism by which pancreatic cancer cells resist Anoikis and metastasize is not well established. Significant proportion of pancreatic cancer cells resisted Anoikis when grown under anchorage-independent conditions. The cells that resisted Anoikis showed higher migratory and invasive characteristics than the cells that were cultured under anchorage-dependent condition. Interestingly, Anoikis-resistant cells exhibited significantly increased expression and phosphorylation of signal transducer and activation of transcription 3 (STAT3) at Tyr 705, as compared to adherent cells. AG 490 and piplartine (PL) induced significant Anoikis in Anoikis-resistant pancreatic cancer cells. Silencing STAT3 not only reduced the capacity of pancreatic cancer cells to resist Anoikis but also reversed its invasive characteristics. Interleukin-6 treatment and overexpression of STAT3 enhanced Anoikis resistance and protected the cells from PL-induced Anoikis. PL-treated cells completely failed to develop tumors when injected subcutaneously in immune-compromised mice. Moreover, these cells also failed to metastasize when injected intravenously. On the other hand, untreated Anoikis-resistant cells not only formed aggressive tumors but also metastasized substantially to lungs and liver when injected intravenously. Metastatic nodules formed by untreated Anoikis-resistant cells in lungs exhibited significant phosphorylation of STAT3 at Tyr705. Taken together, our results established the critical involvement of STAT3 in conferring Anoikis resistance to pancreatic cancer cells and increased metastasis.

  • Critical role of STAT3 in melanoma metastasis through Anoikis resistance
    Oncotarget, 2014
    Co-Authors: Neel M. Fofaria, Sanjay K. Srivastava

    Abstract:

    Anoikis is an anchorage-independent cell death. Resistance to Anoikis is one of the key features of metastatic cells. Here, we analyzed the role of STAT3 in Anoikis resistance in melanoma cells leading to metastasis. When grown under anchorage-independent conditions, significant proportion of cells resisted Anoikis and these resistant cells had higher rate of migration and invasion as compared to the cells grown under anchorage-dependent conditions. The Anoikis resistant cells also had significantly higher expression and phosphorylation of STAT3 at Y705 than the cells that were attached to the basement membrane. STAT3 inhibitors, AG 490 and piplartine (PL) induced Anoikis in a concentration-dependent manner in Anoikis resistant cells. Over-expression of STAT3 or treatment with IL-6 not only increased Anoikis resistance, but also protected the cancer cells from PL-induced Anoikis. On the other hand, silencing STAT3 decreased the potential of cancer cells to resist Anoikis and to migrate. STAT3 knock-down cells and PL treated cells did not form tumors as well as failed to metastasize in SCID-NSG mice as compared to untreated anchorage-independent cells, which formed big tumors and extensively metastasized. In summary, our results for the first time establish STAT3 as a critical player that renders Anoikis resistance to melanoma cells and enhance their metastatic potential.