Docosahexaenoic acid (DHA), an n-3 polyunsaturated fatty acid present in fish oil, may exert cytotoxic and/or cytostatic effects on colon cancer cells when applied individually or in combination with some anticancer drugs. Here we demonstrate a selective ability of subtoxic doses of DHA to enhance antiproliferative and apoptotic effects of clinically useful cytokine TRAIL (tumor necrosis factor-related apoptosis inducing ligand) in cancer but not normal human colon cells. DHA-mediated stimulation of TRAIL-induced apoptosis was associated with extensive engagement of mitochondrial pathway (Bax/Bak activation, drop of mitochondrial membrane potential, cytochrome c release), activation of endoplasmic reticulum stress response (CHOP upregulation, changes in PERK level), decrease of cellular inhibitor of apoptosis protein (XIAP, cIAP1) levels and significant changes in sphingolipid metabolism (intracellular levels of ceramides, hexosyl ceramides, sphingomyelines, sphingosines; HPLC/MS/MS). Interestingly, we found significant differences in representation of various classes of ceramides (especially C16:0, C24:1) between the cancer and normal colon cells treated with DHA and TRAIL, and suggested their potential role in the regulation of the cell response to the drug combination. These study outcomes highlight the potential of DHA for a new combination therapy with TRAIL for selective elimination of colon cancer cells via simultaneous targeting of multiple steps in apoptotic pathways.
- MeSH
- adenokarcinom genetika metabolismus patologie MeSH
- apoptóza účinky léků genetika MeSH
- cytochromy c sekrece MeSH
- inhibitory apoptózy MeSH
- kinasa eIF-2 genetika metabolismus MeSH
- kyseliny dokosahexaenové farmakologie MeSH
- lidé MeSH
- membránový potenciál mitochondrií účinky léků MeSH
- mitochondrie účinky léků metabolismus MeSH
- nádorové buněčné linie MeSH
- nádory tračníku genetika metabolismus patologie MeSH
- protein Bak genetika metabolismus MeSH
- protein TRAIL farmakologie MeSH
- protein X asociovaný s bcl-2 genetika metabolismus MeSH
- regulace genové exprese u nádorů * MeSH
- sfingolipidy chemie klasifikace metabolismus MeSH
- signální transdukce MeSH
- stres endoplazmatického retikula účinky léků MeSH
- synergismus léků MeSH
- transkripční faktor CHOP genetika metabolismus MeSH
- X-vázaný inhibitor apoptózy genetika metabolismus MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
In search for novel strategies in colon cancer treatment, we investigated the unique ability of platinum(IV) complex LA-12 to efficiently enhance the killing effects of tumor necrosis factor-related apoptosis inducing ligand (TRAIL), and compared it with the sensitizing action of cisplatin. We provide the first evidence that LA-12 primes human colon cancer cells for TRAIL-induced cytotoxicity by p53-independent activation of the mitochondrial apoptotic pathway. The cooperative action of LA-12 and TRAIL was associated with stimulation of Bax/Bak activation, drop of mitochondrial membrane potential, caspase-9 activation, and a shift of the balance among Bcl-2 family proteins in favor of the pro-apoptotic members. In contrast to cisplatin, LA-12 was a potent inducer of ERK-mediated Noxa and BimL protein upregulation, and more effectively enhanced TRAIL-induced apoptosis in the absence of Bax. The cooperative action of LA-12 and TRAIL was augmented following the siRNA-mediated silencing of Mcl-1 in both Bax proficient/deficient cells. We newly demonstrated that LA-12 induced ERK-mediated c-Myc upregulation, and proved that c-Myc silencing inhibited the mitochondrial activation and apoptosis in colon cancer cells treated with LA-12 and TRAIL. The LA-12-mediated sensitization to TRAIL-induced apoptosis was demonstrated in several colon cancer cell lines, further underscoring the general relevance of our findings. The selective action of LA-12 was documented by preferential priming of cancer but not normal colon cancer cells to TRAIL killing effects. Our work highlights the promising potential of LA-12 over cisplatin to enhance the colon cancer cell sensitivity to TRAIL-induced apoptosis, and provides new mechanistic insights into their cooperative action.
- MeSH
- amantadin analogy a deriváty farmakologie MeSH
- antitumorózní látky farmakologie MeSH
- apoptóza účinky léků genetika MeSH
- cisplatina farmakologie MeSH
- geny p53 MeSH
- HCT116 buňky účinky léků MeSH
- lidé MeSH
- membránový potenciál mitochondrií účinky léků MeSH
- mitochondrie účinky léků metabolismus MeSH
- nádorové buňky kultivované MeSH
- nádory tračníku farmakoterapie metabolismus patologie MeSH
- organoplatinové sloučeniny farmakologie MeSH
- protein Bak metabolismus MeSH
- protein TRAIL metabolismus farmakologie MeSH
- protein X asociovaný s bcl-2 genetika metabolismus MeSH
- protoonkogenní proteiny c-bcl-2 metabolismus MeSH
- protoonkogenní proteiny c-myc genetika metabolismus MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
