Titanium Tackles the Endoplasmic Reticulum: A First Genomic Study on a Titanium Anticancer Metallodrug
Maya Miller,
Anna Mellul,
Maya Braun,
Dana Sherill-Rofe,
Emiliano Cohen,
Zohar Shpilt,
Irene Unterman,
Ori Braitbard,
Jacob Hochman,
Edit Y. Tshuva,
Yuval Tabach
Affiliations
Maya Miller
Institute of Chemistry, The Hebrew University of Jerusalem, Jerusalem 9190401, Israel; Department of Developmental Biology and Cancer Research, Institute of Medical Research-Israel-Canada, The Hebrew University of Jerusalem, Jerusalem 9112102, Israel
Anna Mellul
Department of Developmental Biology and Cancer Research, Institute of Medical Research-Israel-Canada, The Hebrew University of Jerusalem, Jerusalem 9112102, Israel
Maya Braun
Department of Developmental Biology and Cancer Research, Institute of Medical Research-Israel-Canada, The Hebrew University of Jerusalem, Jerusalem 9112102, Israel
Dana Sherill-Rofe
Department of Developmental Biology and Cancer Research, Institute of Medical Research-Israel-Canada, The Hebrew University of Jerusalem, Jerusalem 9112102, Israel
Emiliano Cohen
Department of Developmental Biology and Cancer Research, Institute of Medical Research-Israel-Canada, The Hebrew University of Jerusalem, Jerusalem 9112102, Israel
Zohar Shpilt
Institute of Chemistry, The Hebrew University of Jerusalem, Jerusalem 9190401, Israel
Irene Unterman
Department of Developmental Biology and Cancer Research, Institute of Medical Research-Israel-Canada, The Hebrew University of Jerusalem, Jerusalem 9112102, Israel
Ori Braitbard
Department of Cell and Developmental Biology, Alexander Silberman Institute of Life Science, The Hebrew University of Jerusalem, Jerusalem 9190401, Israel
Jacob Hochman
Department of Cell and Developmental Biology, Alexander Silberman Institute of Life Science, The Hebrew University of Jerusalem, Jerusalem 9190401, Israel
Edit Y. Tshuva
Institute of Chemistry, The Hebrew University of Jerusalem, Jerusalem 9190401, Israel; Corresponding author
Yuval Tabach
Department of Developmental Biology and Cancer Research, Institute of Medical Research-Israel-Canada, The Hebrew University of Jerusalem, Jerusalem 9112102, Israel; Corresponding author
Summary: PhenolaTi is an advanced non-toxic anticancer chemotherapy; this inert bis(phenolato)bis(alkoxo) Ti(IV) complex demonstrates the intriguing combination of high and wide efficacy with no detected toxicity in animals. Here we unravel the cellular pathways involved in its mechanism of action by a first genome study on Ti(IV)-treated cells, using an attuned RNA sequencing-based available technology. First, phenolaTi induced apoptosis and cell-cycle arrest at the G2/M phase in MCF7 cells. Second, the transcriptome of the treated cells was analyzed, identifying alterations in pathways relating to protein translation, DNA damage, and mitochondrial eruption. Unlike for common metallodrugs, electrophoresis assay showed no inhibition of DNA polymerase activity. Reduced in vitro cytotoxicity with added endoplasmic reticulum (ER) stress inhibitor supported the ER as a putative cellular target. Altogether, this paper reveals a distinct ER-related mechanism by the Ti(IV) anticancer coordination complex, paving the way for wider applicability of related techniques in mechanistic analyses of metallodrugs.
