minocycline and Kidney-Neoplasms

The functional importance of mitochondrial protein translation has been recently documented in the context of various cancers but not renal cell carcinoma (RCC). In lines with these efforts, our work demonstrates that mitochondrial translation inhibition by tigecycline or depletion of EF-Tu mitochondrial translation factor effectively targets RCC and significantly sensitizes RCC response to chemotherapy. We show that antibiotic tigecycline inhibits multiple biological functions of RCC, including growth, colony formation and survival. It also significantly enhances in vitro and in vivo efficacy of paclitaxel in RCC. Tigecycline preferentially inhibits translation of mitochondrial DNA-encoded proteins, activities of mitochondrial respiratory complexes that contain mitochondrially encoded subunits. As a consequence of mitochondrial respiratory chain inhibition, decreased mitochondrial respiration is observed in RCC cells exposed to tigecycline. In contrast, tigecycline is ineffective in RCC ρ0 cells that lack mitochondrial DNA and subsequent mitochondrial respiration, further confirm mitochondrial translation inhibition as the mechanism of tigecycline's action in RCC. Importantly, genetic inhibition of mitochondrial translation by EF-Tu knockdown reproduced the inhibitory effects of tigecycline. Finally, we show the association between mitochondrial translation inhibition and suppression of PI3K/Akt/mTOR signaling pathway. Our work used pharmacological and genetic strategies to demonstrate the important roles of mitochondrial translation in RCC and emphasize the therapeutic value of sensitizing RCC to chemotherapy.

Topics: Animals; Anti-Bacterial Agents; Antineoplastic Agents, Phytogenic; Carcinoma, Renal Cell; Cell Line, Tumor; DNA, Mitochondrial; Humans; Kidney; Kidney Neoplasms; Male; Mice, Inbred BALB C; Minocycline; Mitochondria; Paclitaxel; Peptide Elongation Factor Tu; Protein Biosynthesis; Tigecycline

Topics: Animals; Anti-Bacterial Agents; Carcinoma, Renal Cell; Endothelial Growth Factors; Fibroblast Growth Factor 2; Kidney Neoplasms; Lung Neoplasms; Lymphokines; Matrix Metalloproteinase Inhibitors; Metalloendopeptidases; Mice; Minocycline; Neoplasm Invasiveness; Neoplasm Metastasis; Protease Inhibitors; Statistics, Nonparametric; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors

Degradation of the extracellular matrix by metalloproteinases is a critical phenomenon in cancer invasion and metastasis. Recent studies have revealed that minocycline (minocycline hydrochloride, a tetracycline) suppresses in vivo and in vitro mammalian collagenolytic activity. We investigated whether minocycline inhibited in vitro invasion and experimental pulmonary metastasis in subline-2 of streptozotocin-induced mouse renal adenocarcinoma (MRAC-PM2) cells. In vitro invasion assay demonstrated that treatment with 0.5 microgram/ml or 5.0 micrograms/ml minocycline significantly inhibited the invasion of MRAC-PM2 cells. In addition, intraperitoneal administration of 0.5 mg per mouse minocycline reduced the number of metastatic nodules in the lung when MRAC-PM2 cells were injected intravenously. Minocycline also suppressed type IV collagenolytic activity of the cells. However, the drug did not affect [3H]-thymidine uptake, growth of subcutaneously inoculated cells, attachment to the extracellular matrices, or haptotactic migration of the cells. These results indicated that the inhibitory action of type IV collagen degradation by minocycline can contribute, in part, to suppression of the in vitro invasion and metastatic potential of MRAC-PM2 cells.

Topics: Adenocarcinoma; Animals; Cell Adhesion; Collagen; DNA, Neoplasm; In Vitro Techniques; Kidney Neoplasms; Lung Neoplasms; Mice; Mice, Inbred Strains; Minocycline; Neoplasm Invasiveness; Neoplasm Transplantation; Streptozocin; Tumor Cells, Cultured