Cunninghamella elegans NRRL-1393 is an oleaginous fungus able to synthesize and accumulate unsaturated fatty acids, amongst which the bioactive gamma-linolenic acid (GLA) has potential anti-cancer activities. C. elegans was cultured in shake-flask nitrogen-limited media with either glycerol or glucose (both at ≈60 g/L) employed as the sole substrate. The assimilation rate of both substrates was similar, as the total biomass production reached 13.0–13.5 g/L, c. 350 h after inoculation (for both instances, c. 27–29 g/L of substrate were consumed). Lipid production was slightly higher on glycerol-based media, compared to the growth on glucose (≈8.4 g/L vs. ≈7.0 g/L). Lipids from C. elegans grown on glycerol, containing c. 9.5% w/w of GLA, were transformed into fatty acid lithium salts (FALS), and their effects were assessed on both human normal and cancerous cell lines. The FALS exhibited cytotoxic effects within a 48 h interval with an IC50 of about 60 μg/mL. Additionally, a suppression of migration was shown, as a significant elevation of oxidative stress levels, and the induction of cell death. Elementary differences between normal and cancer cells were not shown, indicating a generic mode of action; however, oxidative stress level augmentation may increase susceptibility to anticancer drugs, improving chemotherapy effectiveness.

The rapid emergence of resistance limits the application of proteasome inhibitors against solid tumors, despite their effectiveness in the treatment of hematological malignancies. Resistant phenotypes are complex and multifaceted, and, thus, the mechanisms involved have not been adequately described. In this study, a Bortezomib-resistant prostate cancer cell line is created by using the PC-3 cell as a prostate carcinoma model of high metastatic potential. The main biochemical differences and adaptations exhibited by the resistant cells revolve around apoptosis evasion, autophagy induction (functioning as a ubiquitin-proteasome system substitute), expression of epithelial-to-mesenchymal transition markers, and increased aggressiveness. Broad-spectrum signaling pathway analyses also reveal an upregulation and activation of Nf-κB, STAT3, cJun, and Elk1 transcription factors in the resistant cells. Additionally, intracellular reactive oxygen species assays reveal a downregulation in resistant cells, which is theorized to be a consequence of metabolic changes, increased autophagic flux, and antioxidative enzyme action. These findings expand our understanding of proteasome inhibitor resistance and highlight key kinases and transcription factors as novel potential therapeutic targets. Effective inhibition of resistance-specific pathways could re-sensitize the cells to proteasome inhibitors, thus surpassing current therapeutic limitations.