Molecular targets for the protodynamic action of cis-urocanic acid in human bladder carcinoma cellsReport as inadecuate

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BMC Cancer

, 10:521

Translational oncology


Backgroundcis-urocanic acid cis-UCA is an endogenous amino acid metabolite capable of transporting protons from the mildly acidic extracellular medium into the cell cytosol. The resulting intracellular acidification suppresses many cellular activities. The current study was aimed at characterizing the molecular mechanisms underlying cis-UCA-mediated cytotoxicity in cultured cancer cells.

Methods5367 bladder carcinoma cells were left untreated or treated with cis-UCA. Cell death was assessed by measuring caspase-3 activity, mitochondrial membrane polarization, formation and release of cytoplasmic histone-associated DNA fragments, and cellular permeabilization. Cell viability and metabolic activity were monitored by colorimetric assays. Nuclear labelling was used to quantify the effects of cis-UCA on cell cycle. The activity of the ERK and JNK signalling pathways was studied by immunoblotting with specific antibodies. Phosphatase activity in cis-UCA-treated cells was determined by assay kits measuring absorbance resulting from the dephosphorylation of an artificial substrate. All statistical analyses were performed using the two-way Student-s t-test p < 0.05.

ResultsHere we report that treatment of the 5637 human bladder carcinoma cells with 2% cis-UCA induces both apoptotic and necrotic cell death. In addition, metabolic activity of the 5637 cells is rapidly impaired, and the cells arrest in cell cycle in response to cis-UCA. Importantly, we show that cis-UCA promotes the ERK and JNK signalling pathways by efficiently inhibiting the activity of serine-threonine and tyrosine phosphatases.

ConclusionsOur studies elucidate how cis-UCA modulates several cellular processes, thereby inhibiting the proliferation and survival of bladder carcinoma cells. These anti-cancer effects make cis-UCA a potential candidate for the treatment of non-muscle invasive bladder carcinoma.

Abbreviationscis-UCAcis-urocanic acid

ERKextracellular signal-regulated kinase

JNKc-Jun N-terminal kinase

MAPKmitogen-activated protein kinase

PARP1polyADP-ribose polymerase-1.

Electronic supplementary materialThe online version of this article doi:10.1186-1471-2407-10-521 contains supplementary material, which is available to authorized users.

Emilia Peuhu, Aura Kaunisto contributed equally to this work.

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Author: Emilia Peuhu - Aura Kaunisto - Jarmo K Laihia - Lasse Leino - John E Eriksson


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