Fumonisin B1 Inhibits Endoplasmic Reticulum Stress Associated-apoptosis After FoscanPDT Combined with C6-Pyridinium Ceramide or Fenretinide

Abstract

Background/Aim Combining an anticancer agent fenretinide (HPR) or C6-pyridinium ceramide (LCL29) with Foscan-mediated photodynamic therapy (FoscanPDT) is expected to augment anticancer benefits of each substance. We showed that treatment with FoscanPDT+HPR enhanced accumulation of C16-dihydroceramide, and that fumonisin B1 (FB), an inhibitor of ceramide synthase, counteracted caspase-3 activation and colony-forming ability of head and neck squamous cell carcinoma (HNSCC) cells. Because cancer cells appear to be more susceptible to increased levels of the endoplasmic reticulum (ER) stress than normal cells, herein we tested the hypothesis that FoscanPDT combined with HPR or LCL29 induces FB-sensitive ER stress-associated apoptosis that affects cell survival. Materials and Methods Using an HNSCC cell line, we determined: cell survival by clonogenic assay, caspase-3 activity by spectrofluorometry, the expression of the ER markers BiP and CHOP by quantitative real-time polymerase chain reaction and western immunoblotting, and sphingolipid levels by mass spectrometry. Results Similar to HPR+FoscanPDT, LCL29+FoscanPDT induced enhanced loss of clonogenicity and caspase-3 activation, that were both inhibited by FB. Our additional pharmacological evidence showed that the enhanced loss of clonogenicity after the combined treatments was singlet oxygen-, ER stress- and apoptosis-dependent. The combined treatments induced enhanced, FB-sensitive, up-regulation of BiP and CHOP, as well as enhanced accumulation of sphingolipids. Conclusion Our data suggest that enhanced clonogenic cell killing after the combined treatments is dependent on oxidative- and ER-stress, apoptosis, and FB-sensitive sphingolipid production, and should help develop more effective mechanism-based therapeutic strategies.

Dihydroceramide desaturase 1 ( DES1 ) promotes anchorage‐independent survival downstream of HER2 ‐driven glucose uptake and metabolism

“…An outstanding question relates to the mechanism by which DES1 promotes AIS and there are a couple of possibilities. Prior studies have shown that loss of DES1 activity can lead to activation of apoptosis, 66–68 autophagy, 46,67 and ER stress pathways 69 . Our studies here suggest that DES1 is not impacting classical anoikis pathways, as DES1 loss did not induce PARP cleavage or increase caspase activity.…”

“…Although the DES1 inhibitors used here, namely 4HPR and SKi-II, are known to affect other targets, our conclusions are strongly supported by genetic loss of function experiments as well as gain of function approaches showing that DES1 is sufficient to drive AIS and enhance in vitro tumorigenicity. Of note, although effects of DES1 inhibitors on cell death and proliferation have been reported, [66][67][68] biological consequences of increased DES1 activity and/or expression are less well studied. Furthermore, our studies offer important context as to when DES1 inhibitors could be particularly effective, that is, in the metastatic setting where AIS is a key biology.…”

Activation of the IRE1α Arm, but not the PERK Arm, of the Unfolded Protein Response Contributes to Fumonisin B1-Induced Hepatotoxicity

“…It has been shown that the induction of apoptosis and autophagy contributed to FB1-induced toxicity [14,[22][23][24][25][26]. We next asked whether the inhibition of ER stress could protect against FB1-induced hepatic apoptosis and autophagy in vivo.…”

The Photosensitizer Temoporfin (mTHPC) – Chemical, Pre‐clinical and Clinical Developments in the Last Decade†‡

“…Sphingolipids and their ceramide subgroup are building blocks of membranes, but also fulfil numerous other functions in the cell and have been shown to be involved in PDT (95,169). In a series of publications, Korbelik and Separovic (95,96,169,195,(273)(274)(275) analyzed the relevance of sphingolipids for PDT with temoporfin and investigated the synergistic effect of combination therapies, e.g. with the ceramide analogue LCL29, the synthetic retinoide derivative fenretinide and a ceramidase inhibitor.…”