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

INSERM, U895, Centre Méditerranéen de Médecine Moléculaire, Biology and Pathologies of Melanocytes, Nice, France.
Oncogene (Impact Factor: 8.46). 06/2011; 30(49):4887-900. DOI: 10.1038/onc.2011.198
Source: PubMed


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.

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Available from: Aude Mallavialle, Mar 03, 2015
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    • "Increased SPARC is associated to poor prognosis in pancreatic adenocarcinoma and to lymph node metastasis in gastric cancers [30]. In melanoma cells SPARC promotes proliferation and survival through akt-dependant regulation of p53 [31]. In a three dimensional context the interaction of fibronectin and alphaV integrin has been associated to increased proliferation in ductal pancreatic carcinoma [32]. "
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    • "Both molecules display similar tumor type specific influences on human tumor tissues [17], [70], [71], [79]–[82]. Both can also exert similar effects on downstream signaling pathways and molecules such as E-Cadherin [12], [83], Src [11], [84], FAK [11], [83], ERK1/2 [11], [85], MMP2 [11], [86], Akt, p53, p21cip1/waf1 [23], [87], [88], and the Rho GTPase family members [12], [84]. Moreover, both genes have been implicated in maintenance of retinal function [5], [89], [90]. "
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    • "SPARC also has potential to act as a regulator of insulin secretion or in maintenance of beta-cell function. It is known to be involved in WNT signalling, which is important in control of cell-cell communication and cellular proliferation and differentiation [18], and also regulates several genes involved in beta-cell development or islet neogenesis [19], [20], [21] and is also known to regulate cell survival [22], [23]. These observations make SPARC an interesting candidate as a modifier of islet insulin secretory capacity, since both destruction and dedifferentiation of beta cells has been described in type 2 diabetes [24], [25]. "
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