Abstract
Adrenocortical carcinoma (ACC) is a very rare endocrine tumour, with variable prognosis, depending on tumour stage and time of diagnosis. However, it is generally fatal, with an overall survival of 5 years from detection. Radiotherapy usefulness for ACC treatment has been widely debated and seems to be dependent on molecular alterations, which in turn lead to increased radio-resistance. Many studies have shown that p53 loss is an important risk factor for malignant adrenocortical tumour onset and it has been reported that somatic mutations in TP53 gene occur in 27 to 70% of adult sporadic ACCs. In this study, we investigated the role of somatic mutations of the TP53 gene in response to ionizing radiation (IR). We studied the status of p53 in two adrenocortical cell lines, H295R and SW-13, harbouring non-functioning forms of this protein, owing to the lack of exons 8 and 9 and a point mutation in exon 6, respectively. Moreover, these cell lines show high levels of p-Akt and IGF2, especially H295R. We noticed that restoration of p53 activity led to inhibition of growth after transient transfection of cells with wild type p53. Evaluation of their response to IR in terms of cell proliferation and viability was determined by means of cell count and TUNEL assay.wtp53 over-expression also increased cell death by apoptosis following radiation in both cell lines. Moreover, RT-PCR and Western blotting analysis of some p53 target genes, such as BCL2, IGF2 and Akt demonstrated that p53 activation following IR led to a decrease in IGF2 expression. This was associated with a reduction in the active form of Akt. Taken together, these results highlight the role of p53 in response to radiation of ACC cell lines, suggesting its importance as a predictive factor for radiotherapy in malignant adrenocortical tumours cases.
Highlights
Adrenocortical carcinoma (ACC) is a very rare endocrine tumour, with an incidence estimated at approximately 1 to 2 cases per 1 million people every year in the general adult population [1,2], while in the infant population of Southern Brazil the frequency of this malignancy is relatively high, ranging from 3,4 to 4,2 per million children [3,4]
We analysed the status of TP53 gene in two human ACC cell lines, H295R and SW-13, and we found that this gene is mutated in both cell lines, which are partially resistant to ionizing radiation (IR) at a dose of 6 Gy, as previously demonstrated [13]
Since we demonstrated that wtp53 is able to reduce cell proliferation and induce apoptosis in ACC cell lines in response to IR, we investigated the effect of p53 activation on IGF2 expression
Summary
Adrenocortical carcinoma (ACC) is a very rare endocrine tumour, with an incidence estimated at approximately 1 to 2 cases per 1 million people every year in the general adult population [1,2], while in the infant population of Southern Brazil the frequency of this malignancy is relatively high, ranging from 3,4 to 4,2 per million children [3,4]. ACCs show variable prognosis, depending on tumour stage and time of diagnosis, they are generally fatal, with an overall survival of 5 years from detection [6]. Frequency of metastasis associated with ACC varies depending on the study, ranging from 30% to 85% of patients with distant metastasis at the time of presentation [7]. Other adjuvant treatment options after complete tumour removal are needed [8,9]
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