Paracrine Apoptotic Effect of p53 Mediated by Tumor Suppressor Par-4

Abstract

Summary The guardian of the genome, p53, is often mutated in cancer and may contribute to therapeutic resistance. As p53 is intact and functional in normal tissues, we harnessed its potential to inhibit the growth of p53-deficient cancer cells. Specific activation of p53 in normal fibroblasts selectively induced apoptosis in p53-deficient cancer cells. This paracrine effect was mediated by p53-dependent secretion of the tumor suppressor Par-4. Accordingly, activation of p53 in normal mice, but not in p53−/− or Par-4−/− mice, caused systemic elevation of Par-4 that induced apoptosis of p53-deficient tumor cells. Mechanistically, p53 induced Par-4 secretion by suppressing the expression of UACA, which sequesters Par-4. Thus, normal cells can be empowered by p53 activation to induce Par-4 secretion for inhibition of therapy-resistant tumors.

Chloroquine-Inducible Par-4 Secretion Is Essential for Tumor Cell Apoptosis and Inhibition of Metastasis

“…We reported previously that Nutlin-3a activated p53 and promoted Par-4 secretion via the BFA-sensitive classical secretory pathway involving the transport of proteins from the endoplasmic reticulum (ER) to the Golgi and onward to the plasma membrane (Burikhanov et al, 2014a). Importantly, p53 function was essential for secretion of Par-4 via the classical pathway (Burikhanov et al, 2014a).…”

“…Importantly, p53 function was essential for secretion of Par-4 via the classical pathway (Burikhanov et al, 2014a). As CQ was known to cause activation of p53 through the ATM-signaling pathway (Sohn et al, 2002; Loehberg et al, 2007; Maclean et al, 2008), we tested whether p53 function was required for CQ-induced Par-4 secretion.…”

“…Elevation of extracellular Par-4 in cell-culture conditioned medium (CM) induced apoptosis of cancer cell cultures (Burikhanov et al, 2009, 2013, 2014a, 2014b), and systemic elevation of Par-4 in mice inhibited growth of tumors (Zhao et al, 2011). Using a chemical biology approach to elevate the secretion of Par-4 from normal cells, we identified a 3-arylquinoline, Arylquin-1, as a potent Par-4 secretagogue in normal cell cultures and mouse models (Burikhanov et al, 2014b).…”

Development of 6 H -chromeno[3,4- c ]pyrido[3′,2′:4,5]thieno[2,3- e ]pyridazin-6-ones as Par-4 secretagogues

“…1, 2 Par-4 binds to Glucose-regulated Protein-78 receptor (GRP78) found exclusively on cancer cells and triggers apoptosis. 2 Unfortunately, normal cells, even though they far outnumber cancer cells, sequester endogenous Par-4 and export it only at low levels.…”

Papel da expressão celular e extracelular do Par-4 na formação tumoral e sensibilidade a droga

“…Ainda que sua identificação tenha ocorrido em meio à investigação de células de câncer, especificamente células de tumor de próstata, sua relação se estende para outras doenças, como no caso das doenças neurodegenerativas MATTSON et al, 1999;XIE, 2005 BARRADAS et al, 1999;GOSWAMI et al, 2005;QIU et al, 1999 O envolvimento de Par-4 no processo de morte celular já é muito bem estabelecido na literatura, sendo essa sua principal função biológica (BURIKHANOV et al, 2013(BURIKHANOV et al, , 2014GURUMURTHY;RANGNEKAR, 2004;RANGNEKAR, 1998;SELLS et al, 1997). Um dos grandes objetivos deste trabalho foi avaliar se a alteração na expressão de Par-4 seria capaz de modular a sensibilidade da resposta das células MDA-MB-231 frente a um estímulo apoptótico.…”