New ruthenium-xanthoxylin complex eliminates colorectal cancer stem cells by targeting the heat shock protein 90 chaperone.
Luciano de S SantosValdenizia R SilvaMaria V L de CastroRosane B DiasLudmila de F ValverdeClarissa A G RochaMilena B P SoaresClaudio A QuadrosEdjane R Dos SantosRegina M M OliveiraRose M CarlosPaulo C L NogueiraDaniel Pereira BezerraPublished in: Cell death & disease (2023)
In this work, we describe a novel ruthenium-xanthoxylin complex, [Ru(phen) 2 (xant)](PF 6 ) (RXC), that can eliminate colorectal cancer (CRC) stem cells by targeting the chaperone Hsp90. RXC exhibits potent cytotoxicity in cancer cell lines and primary cancer cells, causing apoptosis in HCT116 CRC cells, as observed by cell morphology, YO-PRO-1/PI staining, internucleosomal DNA fragmentation, mitochondrial depolarization, and PARP cleavage (Asp214). Additionally, RXC can downregulate the HSP90AA1 and HSP90B1 genes and the expression of HSP90 protein, as well as the expression levels of its downstream/client elements Akt1, Akt (pS473), mTOR (pS2448), 4EBP1 (pT36/pT45), GSK-3β (pS9), and NF-κB p65 (pS529), implying that these molecular chaperones can be molecular targets for RXC. Moreover, this compound inhibited clonogenic survival, the percentage of the CRC stem cell subpopulation, and colonosphere formation, indicating that RXC can eliminate CRC stem cells. RXC reduced cell migration and invasion, decreased vimentin and increased E-cadherin expression, and induced an autophagic process that appeared to be cytoprotective, as autophagy inhibitors enhanced RXC-induced cell death. In vivo studies showed that RXC inhibits tumor progression and experimental metastasis in mice with CRC HCT116 cell xenografts. Taken together, these results highlight the potential of the ruthenium complex RXC in CRC therapy with the ability to eliminate CRC stem cells by targeting the chaperone Hsp90.
Keyphrases
- heat shock protein
- cell death
- cell cycle arrest
- heat shock
- stem cells
- poor prognosis
- signaling pathway
- cell therapy
- oxidative stress
- pi k akt
- single cell
- induced apoptosis
- diabetic rats
- binding protein
- endoplasmic reticulum stress
- heat stress
- squamous cell carcinoma
- gene expression
- adipose tissue
- papillary thyroid
- insulin resistance
- type diabetes
- lps induced
- climate change
- immune response
- dna methylation
- risk assessment
- transcription factor