A Novel Interaction between Procaspase 8 and SPARC Enhances Apoptosis and Potentiates Chemotherapy Sensitivity in Colorectal Cancers

Tang, Michelle; Tai, Isabella T.

doi:10.1074/jbc.m704459200

Cited by 74 publications

(73 citation statements)

References 39 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…In this study we identified further components of membrane microdomain responsible for the cytotoxic effect of WIN/TRAIL treatment. In fact, in our experimental model, similarly to that observed by Tang and Tai (24) in colorectal cancer, the activation of caspase-8 seemed to be related with the interaction with SPARC as demonstrated by us through co-immunoprecipitation analysis. The interaction was abrogated after WIN/TRAIL treatment owing to the cleavage and activation of caspase-8.…”

Section: Discussionsupporting

confidence: 58%

The secreted protein acidic and rich in cysteine is a critical mediator of cell death program induced by WIN/TRAIL combined treatment in osteosarcoma cells

Notaro

Sabella

Pellerito

et al. 2015

International Journal of Oncology

View full text Add to dashboard Cite

Abstract. Secreted protein acidic and rich in cysteine (SPARC) is a multi-functional protein which modulates cell-cell and cell-matrix interactions. In cancer cells, SPARC behaves as a tumor promoter in a number of tumors, but it can also act as a tumor suppressor factor. Our previous results showed that the synthetic cannabinoid WIN55,212-2 (WIN), a potent cannabinoid receptor agonist, is able to sensitize osteosarcoma MG63 cells to TNF-related apoptosis-inducing ligand (TRAIL)-induced apoptosis which is accompanied with endoplasmic reticulum (ER)-stress induction and the increase in autophagic markers. In the present investigation, we studied the role of SPARC in WIN/TRAIL-induced apoptosis demonstrating that WIN increased the level of SPARC protein and mRNA in a time-dependent manner. This event was functional to WIN/TRAIL-dependent apoptosis as demonstrated by RNA interfering analysis which indicated that SPARC-silenced cells were less sensitive to cytotoxic effects induced by the combined treatment. Our experiments also demonstrate that SPARC interacts with caspase-8 thus probably favoring its translocation to plasma membrane and the activation of extrinsic apoptotic pathway. In conclusion, to the best of our knowledge, our results are the first to show that WIN-dependent increase in the level of SPARC plays a critical role in sensitizing osteosarcoma cells to TRAIL action. IntroductionOsteosarcoma is the most common form of primary bone malignancy, which occurs predominantly in infants and adolescents (1). It represents the prevalent cause of cancerrelated death for children with an incidence of 4-5 cases/10 8 . Patients with osteosarcoma are routinely treated by combining surgery and high-dose chemotherapy and this has significantly improved the 5-year survival rate over time. Nevertheless, osteosarcoma shows high propensity to metastasize and invade surrounding tissue, the lung being the most common site of initial metastatic disease or, less frequently, the other bones (2). Therefore, it is important to identify novel therapeutic strategies which can improve the general conditions and the overall survival rate of patients with osteosarcoma. SPARC (secreted protein acidic and rich in cysteine) also called Osteonectin or BM-40, is a non-structural matricellular glycoprotein expressed in a variety of mammalian tissues (3,4). The effects of SPARC on cell behaviour are highly tissue specific and concern modification of cell shape, migration, proliferation, differentiation and survival (5-9). SPARC is also known to modulate cell-cell and cell-matrix interactions, and to influence de-adhesive and cell growth regulatory properties (10). Moreover, its expression is related to the ability to regulate processes such as bone formation, fibrosis and tissue repair (11). SPARC is differentially expressed in various tumors including breast and colorectal cancers, melanoma or glioma (12-17). Many studies show that in cancer cells SPARC modulates proliferation, apoptosis, invasion and angiogenesis. Its overexpression can...

show abstract

Section: Discussionsupporting

confidence: 58%

The secreted protein acidic and rich in cysteine is a critical mediator of cell death program induced by WIN/TRAIL combined treatment in osteosarcoma cells

Notaro

Sabella

Pellerito

et al. 2015

International Journal of Oncology

View full text Add to dashboard Cite

show abstract

“…Thus, the stress protection function of SPARC appears to be evolutionarily conserved between flies and humans. On the other hand, there is evidence in some contexts that SPARC induces apoptosis in ovarian cancer cells (Yiu et al, 2001) and modulates sensitivity to chemotherapy in colon cancer cells by enhancing apoptosis (Tang and Tai, 2007).…”

Section: Discussionmentioning

confidence: 99%

SPARC functions as an anti-stress factor by inactivating p53 through Akt-mediated MDM2 phosphorylation to promote melanoma cell survival

et al. 2011

View full text Add to dashboard Cite

Aberrant expression of Secreted Protein Acidic and Rich in Cysteine (SPARC)/osteonectin has been associated with an invasive tumor cell phenotype and poor outcome in human melanomas. Although it is known that SPARC controls melanoma tumorigenesis, the precise role of SPARC in melanoma cell survival is still unclear. Here, we show that SPARC has a cell-autonomous survival activity, which requires Akt-dependent regulation of p53. Suppression of SPARC by RNA interference in several human melanoma cells and xenografted A375 tumors triggers apoptotic cell death through the mitochondrial intrinsic pathway and activation of caspase-3. Cell death induced by depletion of SPARC is dependent on p53 and induction of Bax, and results in the generation of ROS. Stabilization of p53 in SPARC-depleted cells is associated with a decrease in Akt-mediated activating phosphorylation of MDM2. Inhibition of Akt signaling pathway is important for the observed changes as overexpression of constitutively active Akt protects cells against apoptosis induced by SPARC depletion. Conversely, increased expression of SPARC stimulates Akt and MDM2 phosphorylation, thus facilitating p53 degradation. Finally, we show that overexpression of SPARC renders cells more resistant to the p53-mediated cytotoxic effects of the DNA-damaging drug actinomycin-D. Our study indicates that SPARC functions through activation of Akt and MDM2 to limit p53 levels and that acquired expression of SPARC during melanoma development would confer survival advantages through suppression of p53-dependent apoptotic pathways.

show abstract

“…Of note, the EC domain binds components of the extracellular matrix and is responsible for mediating many of SPARC's extracellular effects (24). However, there is compelling evidence that SPARC might also exert intracellular functions (20,37). Given the significant role of SPARC in the resistance of IM-R cells, we investigated which domain of the protein is needed for this activity.…”

Section: Forced Expression Of Sparc In Im-s Cells Mitigates Imatinib-mentioning

confidence: 99%

Persistent Activation of the Fyn/ERK Kinase Signaling Axis Mediates Imatinib Resistance in Chronic Myelogenous Leukemia Cells through Upregulation of Intracellular SPARC

et al. 2010

View full text Add to dashboard Cite

SPARC is an extracellular matrix protein that exerts pleiotropic effects on extracellular matrix organization, growth factor availability, cell adhesion, differentiation, and immunity in cancer. Chronic myelogenous leukemia (CML) cells resistant to the BCR-ABL inhibitor imatinib (IM-R cells) were found to overexpress SPARC mRNA. In this study, we show that imatinib triggers SPARC accumulation in a variety of tyrosine kinase inhibitor (TKI)-resistant CML cell lines. SPARC silencing in IM-R cells restored imatinib sensitivity, whereas enforced SPARC expression in imatinib-sensitive cells promoted viability as well as protection against imatinib-mediated apoptosis. Notably, we found that the protective effect of SPARC required intracellular retention inside cells. Accordingly, SPARC was not secreted into the culture medium of IM-R cells. Increased SPARC expression was intimately linked to persistent activation of the Fyn/ERK kinase signaling axis. Pharmacologic inhibition of this pathway or siRNA-mediated knockdown of Fyn kinase resensitized IM-R cells to imatinib. In support of our findings, increased levels of SPARC mRNA were documented in blood cells from CML patients after 1 year of imatinib therapy compared with initial diagnosis. Taken together, our results highlight an important role for the Fyn/ERK signaling pathway in imatinib-resistant cells that is driven by accumulation of intracellular SPARC.

show abstract

A Novel Interaction between Procaspase 8 and SPARC Enhances Apoptosis and Potentiates Chemotherapy Sensitivity in Colorectal Cancers

Cited by 74 publications

References 39 publications

The secreted protein acidic and rich in cysteine is a critical mediator of cell death program induced by WIN/TRAIL combined treatment in osteosarcoma cells

The secreted protein acidic and rich in cysteine is a critical mediator of cell death program induced by WIN/TRAIL combined treatment in osteosarcoma cells

SPARC functions as an anti-stress factor by inactivating p53 through Akt-mediated MDM2 phosphorylation to promote melanoma cell survival

Persistent Activation of the Fyn/ERK Kinase Signaling Axis Mediates Imatinib Resistance in Chronic Myelogenous Leukemia Cells through Upregulation of Intracellular SPARC

Contact Info

Product

Resources

About