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.
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.
|Amatangelo, Michael D; Quek, Lynn; Shih, Alan et al. (2017) Enasidenib induces acute myeloid leukemia cell differentiation to promote clinical response. Blood 130:732-741|
|Delaney, Joe Ryan; Patel, Chandni B; Willis, Katelyn McCabe et al. (2017) Haploinsufficiency networks identify targetable patterns of allelic deficiency in low mutation ovarian cancer. Nat Commun 8:14423|
|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|
|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|
|Shen, W; Chang, A; Wang, J et al. (2015) TIFA, an inflammatory signaling adaptor, is tumor suppressive for liver cancer. Oncogenesis 4:e173|
|Young, Shanique A; McCabe, Katelyn E; Bartakova, Alena et al. (2015) Integrin ?4 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|
|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|
|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|
|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|
Showing the most recent 10 out of 31 publications