The p53/p21Cip1/ Waf1 pathway mediates the effects of SPARC on melanoma cell cycle progression.
Secreted protein acidic and rich in cysteine (SPARC), or osteonectin, belongs to the family of matricellular proteins that modulate cell-matrix interactions and cellular functions. SPARC is highly expressed in melanoma, and we reported that SPARC promotes epithelial/mesenchymal-like changes and cell migration. Here, we used siRNA and conditional shRNA to investigate the contribution of tumor-derived SPARC to melanoma cell growth in vitro and in vivo. We found that depletion of SPARC induces G2/M cell cycle arrest and tumor growth inhibition with activation of p53 and induction of p21(Cip1/Waf1) acting as a checkpoint, preventing efficient mitotic progression. In addition, we demonstrate that reduced mesenchymal features and the invasive potential of SPARC-silenced cells are independent of p21(Cip1/Waf1) induction and cell cycle arrest. Importantly, overexpression of SPARC reduces p53 protein levels and leads to an increase in cell number during exponential growth. Our findings indicate that in addition to its well-known function as a mediator of melanoma cell migration and tumor-host interactions, SPARC regulates, in a cell-autonomous manner, cell cycle progression and proliferation through the p53/p21(Cip1/Waf1) pathway.
Fenouille
Nina
N
INSERM, U895, University of Nice-Sophia Antipolis, Nice, France.
Robert
Guillaume
G
Tichet
Mélanie
M
Puissant
Alexandre
A
Dufies
Maeva
M
Rocchi
Stéphane
S
Ortonne
Jean-Paul
JP
Deckert
Marcel
M
Ballotti
Robert
R
Tartare-Deckert
Sophie
S
D000818:Animals; D002453:Cell Cycle; D002465:Cell Movement; D049109:Cell Proliferation; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism*; D016195:G2 Phase; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008545:Melanoma / Q000235:genetics / Q000473:pathology*; D051379:Mice; D051739:Microphthalmia-Associated Transcription Factor / Q000378:metabolism; D008938:Mitosis; D008954:Models, Biological; D009361:Neoplasm Invasiveness; D015676:Osteonectin / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; C497234:MITF protein, human; D051739:Microphthalmia-Associated Transcription Factor; D015676:Osteonectin; D016159:Tumor Suppressor Protein p53