Abstract
KP1019 ([trans-RuCl4(1H-indazole)2]; FFC14A) is one of the promising ruthenium-based anticancer drugs undergoing clinical trials. Despite the pre-clinical and clinical success of KP1019, the mode of action and various factors capable of modulating its effects are largely unknown. Here, we used transcriptomics and genetic screening approaches in budding yeast model and deciphered various genetic targets and plethora of cellular pathways including cellular signaling, metal homeostasis, vacuolar transport, and lipid homeostasis that are primarily targeted by KP1019. We also demonstrated that KP1019 modulates the effects of TOR (target of rapamycin) signaling pathway and induces accumulation of neutral lipids (lipid droplets) in both yeast and HeLa cells. Interestingly, KP1019-mediated effects were found augmented with metal ions (Al3+/Ca2+/Cd2+/Cu2+/Mn2+/Na+/Zn2+), and neutralized by Fe2+, antioxidants, osmotic stabilizer, and ethanolamine. Additionally, our comprehensive screening of yeast histone H3/H4 mutant library revealed several histone residues that could significantly modulate the KP1019-induced toxicity. Altogether, our findings in both the yeast and HeLa cells provide molecular insights into mechanisms of action of KP1019 and various factors (chemical/genetic/epigenetic) that can alter the therapeutic efficiency of this clinically important anticancer drug.
Highlights
Cancer is an extremely diverse disease characterized by uncontrolled proliferation of abnormal cells that expands into surrounding tissues
We found that the processes related to energy, metabolism, protein synthesis, proteins with binding function, subcellular localization, cell rescue and defense were enriched significantly in KP1019 transcriptome (Figure 1C)
Our functional enrichment analysis showed that genes belonging to cell cycle checkpoint, DNA damage repair, ribosomal biogenesis and translational control were significantly enriched in induced transcriptome (Supplementary Table 3), whereas the genes involved in cell morphogenesis, cytokinesis, transcription, and protein binding were enriched in repressed transcriptome of KP1019 (Supplementary Table 4)
Summary
Cancer is an extremely diverse disease characterized by uncontrolled proliferation of abnormal cells that expands into surrounding tissues. The major factors for oncogenic transformation and cancer development include genetic changes in the proto-oncogenes, tumor suppressor genes, and DNA repair genes [1, 2], and the aberrant pattern in epigenetic mechanisms such as DNA methylation and histone modifications [3, 4]. Alphalist), combating cancer is troublesome due to their distinctive genetic and phenotypic heterogeneity, failure in early detection, inefficient chemotherapy treatment and its associated severe adverse effects, and development of drug-resistance. The failure to decipher and target the multiple underlying pathways of molecular carcinogenesis is a major challenge for anticancer drug development. Recent efforts are being made towards developing additional therapeutic molecules targeting the plethora of cancer mechanisms to achieve higher therapeutic efficiency (specific to cancer cells) with lesser or no adverse effects [5]
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