TARGETTING OF MITOCHONDRIAL PEPTIDE HUMANIN TO IMPROVE CHEMOSENSITIVITY IN GLIOBLASTOMA CELLS

PEÑA AGUDELO, JORGE A.; PIDRE, MATÍAS LUIS; ASAD, ANTONELA S.; GARCIA FALLIT, MATÍAS; PÉREZ KUPER, MELANIE; NICOLA CANDIA, ALEJANDRO JAVIER; GLIENKE, LEILANE; SAGRIPANTI SOFÍA; MARCHESINI, ABRIL; AMORÓS MORALES, LESLIE C.; VERA, MARIANA B.; GONZALEZ, NAZARENO; VIDELA-RICHARDSON, GUILLERMO A.; SEILICOVICH, ADRIANA; CANDOLFI, MARIANELA

Mar del Plata

Congreso; Reunión de Sociedades de Biociencias 2022 (SAIC, SAI, SAFis); 2022

SAIC

Humanin (HN) is amitochondrial peptide with a robust cytoprotective many cell types.HN can interact with proteins of the bcl-2 family or be released andbind with two membrane receptors: a trimetric receptor, and the FPR-2receptor. HN protects normal tissues from chemotherapy, and theadministration of HN analogs has been proposed as a therapeuticapproach for degenerative diseases. However, its role on thepathogenesis of cancer is poorly understood. Here we aimed toevaluate whether HN affects chemo-resistance of glioblastoma (GBM)cells. We first assessed the effect of chemotherapy on HN expressionin murine (GL26) and human (U251) GBM cell lines, as well as inprimary cultures from GBM biopsies. By immunofluorescence we observedthat cisplatin upregulates HN in all the cells evaluated. To analyzethe effect of HN on chemotherapeutic cytotoxicity, we used a HNanalog peptide (HNG). In human GBM cells we observed that HNGabolished the cytotoxic and antiproliferative effect of cisplatin,restoring viability and clonogenic capacity (Two-way ANOVA p<0.05).Blockade HN interaction with the FPR-2 receptor, using a specificantagonist (WRW4), limited the cytoprotective function of bothendogenous and exogenous HN in human GBM cells exposed to cisplatin,as assessed by MTT assay and BrdU incorporation (Two-way ANOVAp<0.05). To explore the effect of endogenous HN on GBM cellchemosensitivity, we developed a baculoviral vector encoding aHN-specific shRNA for the transcriptional silencing of itsexpression. These vectors showed excellent transduction efficiency inthese cells. We observed that the inhibition of endogenous HN exertsan inhibitory effect on the viability of GBM cells and increasestheir sensitivity to cisplatin. Our study suggests that HN favorschemoresistance in GBM cells and that it could hold value as atherapeutic target to improve their response to conventionaltreatment.p { line-height: 115%; text-align: left; orphans: 2; widows: 2; margin-bottom: 0.25cm; direction: ltr; background: transparent }p.western { so-language: es-AR }