Caspase 8 and Integrins in Tumor Progression During the previous funding period, we demonstrated that caspase 8 association with unligated integrins in vivo promoted apoptosis, and that down-regulation of caspase 8 or integrins in neuroblastoma promoted tumor metastasis. Confirming the roll of apoptosis in these studies, we made the paradoxical observation that, among apoptosis-resistant cells, the expression of caspase 8 significantly enhanced integrin-mediated migration in vitro and metastasis in vivo. The overall goal of this proposal is therefore to understand how caspase 8 apoptotic vs nonapoptotic function is regulated. As an initiator caspase, caspase 8 triggers apoptosis downstream of death receptors, toll-like receptors and integrins. Its expression is frequently lost among aggressive neuroblastoma and other neuroendocrine tumors. This has prompted clinical strategies seeking to restore or amplify its expression. However, caspase 8 is not sufficient for apoptosis, but requires a compliant downstream caspase cascade. Among apoptosis-compromised cells, we provide evidence that caspase 8 expression actually functions to enhance tumor metastasis. This surprising result warrants reconsideration of the concept that simple upregulation of caspase 8 is universally beneficial;rather, it may exacerbate disease progression. While nonapoptotic functions of caspase 8 within the immune and vascular compartments are known, the mechanisms committing caspase 8 to these functions are not. Here, we provide preliminary results showing that enhanced cell migration occurs concurrent with caspase 8 tyrosine phosphorylation and localization in focal adhesion contacts following integrin ligation.
AIM 1 of this proposal will characterize the specific caspase 8 tyrosine residues phosphorylated during adhesion, and identify those critical for migration.
AIM 2 will evaluate which tyrosine residues influence caspase 8 catalytic and proapoptotic activities, including protein-protein interactions. Finally, AIM 3 will test the impact of these regulatory tyrosine residues on disease progression in vivo. Together, the results of these studies will reveal molecular mechanisms of caspase 8 regulation important for the development of anti-metastatic therapies.

Public Health Relevance

The protein caspase 8 is well known to be involved in programmed cell death, and its expression is suppressed among aggressive neuroendocrine tumors. However, caspase 8 can also promote cell migration, and we show that it actually enhances the spread of death-resisting cells, which may explain why it is frequently upregulated in carcinoma. This proposal seeks to understand the molecular mechanisms that control caspase 8 switching between these two roles.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01CA107263-11
Application #
8657821
Study Section
Tumor Microenvironment Study Section (TME)
Program Officer
Jhappan, Chamelli
Project Start
Project End
Budget Start
Budget End
Support Year
11
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of California San Diego
Department
Pathology
Type
Schools of Medicine
DUNS #
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Davis, Mitzie-Ann; Delaney, Joe R; Patel, Chandni B et al. (2016) Nelfinavir is effective against human cervical cancer cells in vivo: a potential treatment modality in resource-limited settings. Drug Des Devel Ther 10:1837-46
Zhang, Yan; Shen, Long; Stupack, Dwayne G et al. (2016) JMJD3 promotes survival of diffuse large B-cell lymphoma subtypes via distinct mechanisms. Oncotarget 7:29387-99
Young, Shanique A; McCabe, Katelyn E; Bartakova, Alena et al. (2015) Integrin α4 Enhances Metastasis and May Be Associated with Poor Prognosis in MYCN-low Neuroblastoma. PLoS One 10:e0120815
Delaney, Joe R; Patel, Chandni; McCabe, Katelyn E et al. (2015) A strategy to combine pathway-targeted low toxicity drugs in ovarian cancer. Oncotarget 6:31104-18
Shen, W; Chang, A; Wang, J et al. (2015) TIFA, an inflammatory signaling adaptor, is tumor suppressive for liver cancer. Oncogenesis 4:e173
Sayyah, Jacqueline; Bartakova, Alena; Nogal, Nekeisha et al. (2014) The Ras-related protein, Rap1A, mediates thrombin-stimulated, integrin-dependent glioblastoma cell proliferation and tumor growth. J Biol Chem 289:17689-98
McCabe, K E; Bacos, K; Lu, D et al. (2014) Triggering necroptosis in cisplatin and IAP antagonist-resistant ovarian carcinoma. Cell Death Dis 5:e1496
Cheresh, David A; Stupack, Dwayne G (2014) Tumor angiogenesis: putting a value on plastic GEMMs. Circ Res 114:9-11
Graf, R P; Keller, N; Barbero, S et al. (2014) Caspase-8 as a regulator of tumor cell motility. Curr Mol Med 14:246-54
Díaz, Jorge; Mendoza, Pablo; Ortiz, Rina et al. (2014) Rab5 is required in metastatic cancer cells for Caveolin-1-enhanced Rac1 activation, migration and invasion. J Cell Sci 127:2401-6

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