Povezave med razgradnjo membran, metabolizmom lipidov in odpornostjo rakavih celic na s stradanjem inducirano celično smrt

Holc, Tea (author), Pungerčar, Jože (mentor), Petan, Toni (comentor)

Delovanje človeške sekretorne fosfolipaze A2 skupine X (hGX sPLA2) v visoko tumorigenih celicah raka dojke MDA-MB-231 sproži kopičenje lipidnih kapljic (LK), pospešitev oksidacije maščobnih kislin (MK) ter spremembe v celični signalizaciji. Te spremembe omogočajo preživetje celic raka dojke, ko so le-te izpostavljene metaboličnemu stresu zaradi dolgotrajnega gojenja v odsotnosti seruma. Podobne učinke na preživetje celic in kopičenje LK ima oleinska kislina (OA), ki je eden glavnih produktov encimskega delovanja hGX sPLA2. V sklopu tega magistrskega dela smo ugotovili, da hGX sPLA2 in OA omogočita preživetje celic raka dojke tudi pri drugih vrstah metaboličnega stresa. Pri tem smo opazili, da je prisotnost glukoze nujen (in zadosten) pogoj za pozitiven vpliv hGX sPLA2 na preživetje celic. Prav tako smo s pomočjo pretočne citometrije ugotovili, da imata hGX sPLA2 in OA raznolike učinke na tvorbo LK in preživetje različnih rakavih celic. V nevroblastomnih celicah SH-SY5Y in celicah kolorektalnega raka CaCo-2 namreč inducirata nastanek LK, ne preprečita pa s stradanjem inducirane celične smrti. Presenetljivo pa smo tudi ugotovili, da v gostih kulturah celic raka materničnega vratu HeLa hGX sPLA2 celo zmanjša vsebnost LK, OA pa na tvorbo LK ne vpliva. Rezultati našega dela kažejo, da sta vpliv hGX sPLA2 na tvorbo LK in vloga LK pri preživetju celic tekom stresa raznoliki in močno odvisni od specifičnih lastnosti različnih vrst rakavih celic.

• Language: Slovenian
• Keywords: sekretorna fosfolipaza A2, MDA-MB-231, CaCo-2, SH-SY5Y, HeLa, metabolizem lipidov, pretočna citometrija
• Work type: Master's thesis/paper
• Organization: BF - Biotechnical Faculty
• Year: 2018
• PID: 20.500.12556/RUL-100054
• COBISS.SI-ID: 4661071
• Publication date in RUL: 01.03.2018

Secondary language

• Language: English
• Title: Interactions between cell membrane degradation, lipid metabolism and cancer cell resistance to starvation-induced cell death

Abstract

The human group X secreted phospholipase A2 (hGX sPLA2) induces lipid droplets (LD) accumulation, accelerates fatty acid (FA) oxidation and induces changes in cell signaling in the highly tumorigenic MDA-MB-231 breast cancer cells. These changes protect the cells from serum withdrawal-induced cell death. Oleic acid (OA), which is one of the main products of hGX sPLA2 enzymatic activity, shows similar effects on LD formation and MDA-MB-231 cell survival. Here we show that hGX sPLA2 and OA promote MDA-MB-231 cell survival also during other types of metabolic stress. We found that the presence of glucose in the medium is necessary (and sufficient) for the pro-survival effects of hGX sPLA2. Using flow cytometry, we found that hGX sPLA2 and OA display diverse, even opposing effects on different cancer cells. hGX sPLA2 and OA induced LD accumulation in CaCo-2 colorectal cancer and SH-SY5Y neuroblastoma cell lines, but failed to reduce starvation-induced cell death. Surprisingly, hGX sPLA2 even reduced LD accumulation in a dense culture of HeLa cervical cancer cells, whereas OA had no effect. Our results suggest that the effects of hGX sPLA2 on LD metabolism and the role of LDs in cell survival during stress are diverse and depend strongly on the specific characteristics of the cancer cell type in question.

• Keywords: secreted phospholipase A2, MDA-MB-231, CaCo-2, SH-SY5Y, HeLa, lipid metabolism, flow cytometry