SP600125, a new p53 selective anticancer drug: effects on poorly differentiated thyroid cancers

Elisa Stellaria Grassi; Valeria Vezzoli; Irene Negri; Luca Persani

doi:10.1530/endoabs.32.OC3.3

OC3.3

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Endocrine Abstracts (2013) 32 OC3.3 | DOI: 10.1530/endoabs.32.OC3.3

ECE2013 Oral Communications Thyroid (6 abstracts)

ESE Young Investigator Award

Elisa Stellaria Grassi ¹ , Valeria Vezzoli ² , Irene Negri ³ & Luca Persani ^1,

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¹Università degli Studi di Milano, Dipartimento di Scienze Cliniche e di Comunità, Milan, Italy; ²Istituto Auxologico Italiano, IRCCS, Laboratory of Endocrine and Metabolic Research, Milan, Italy; ³Università degli Studi di Milano, Milan, Italy; ⁴Istituto Auxologico Italiano, IRCCS, Division of Endocrine and Metabolic Diseases, Milan, Italy.

Poorly differentiated thyroid cancers are associated with variable types of p53 function derangements and bad prognosis due to the lack of effective treatments. SP600125 is a widely used JNK-inhibitor which recently showed anticancer properties in a p53 related way. Here, we tested the effect of SP600125 on four different thyroid cancer cell lines derived from PDTCs and ATCs with different p53 status.

We analyzed the effects on cellular replication and apoptosis, changes in morphology or intracellular pathway activities.

Our results show that SP600125 is able to suppress the growth of the three p53-mutated cell lines but not of the p53-null one with significant results after 48 h of incubation and EC50 of 1.3–8.4 μM. This effect is accompanied by a slight caspase 3 activation confirmed by functional assay and western-blotting.

The growth inhibition is correlated with an increase of p21 expression levels of more than 3-fold and a 2-fold increase in nuclear dimensions, thus consistent with significant effects on cell cycle progression and DNA accumulation.

Moreover, we observe that SP600125 treatment in the p53-mutated cells causes polymerized tubulin stabilization, as shown by the relative increase of polymer versus monomer form; this is accompanied by increased polymerized tubulin acetylation, a marker of microtubules stability. Confocal microscopy showed morphological alteration of treated cells as well as differences in acetylated tubulin distribution, with a switch from physiological perinuclear organization to cytoplasmic distibution. These alterations correlate with an increase of cytoplasmic and nuclear area, with variations in p53 and JNK subcellular localization.

All together these data confirm that SP600125 acts in a p53-dependent way and it’s able to induce cell growth arrest with significant effects on nuclear and cell division, microtubule organization and intracellular protein distribution in a subgroup PDTC cells. SP600125 appears a reliable candidate drug for PDTCs harbouring p53 mutations.