Molecular markers of DNA damage and repair in cervical cancer patients treated with cisplatin neoadjuvant chemotherapy: an exploratory study

REAL N.; CASTRO G. N.; CUELLO CARRION F. D.; PERINETTI C.; ROHRICH H.; CAYADO-GUTIÉRREZ N.; GUERREO-GIMÉNEZ M. E.; CIOCCA D. R.

CELL STRESS & CHAPERONES.

SPRINGER

Lugar: Berlin; Año: 2017

1355-8145

Neoadjuvant (or induction) chemotherapy can be used for cervical cancer patients with locally advanced disease; this treatment is followed by radical surgery and/or radiation therapy. Cisplatin is considered to be the most active platinum agent drug for this cancer, with a response rate of 20%. In order to understand how the cisplatin treatment affects the stress response, in this work we performed an exploratory study to analyze a number of stress proteins before and after cisplatin neoadjuvant chemotherapy. The study involved 14 patients; the pre- and post-chemotherapy paired biopsies were examined by hematoxylin and eosin staining and by immunohistochemistry. The proteins evaluated were: p53, P16/INK4A, MSH2, NUPR1 (Nuclear Protein, Transcriptional Regulator, 1), and HSPB1 (total: HSPB1/t and phosphorylated: HSPB1/p). These proteins were selected because there is previous evidence of their relationship with drug resistance. The formation of platinum-DNA adducts was also studied. There was a great variation in the expression levels of the mentioned proteins in the pre-chemotherapy biopsies. After chemotherapy p53 was not significantly affected by cisplatin, as well as P16/INK4A and MSH2 while nuclear NUPR1 content tended to decrease (p=0.056). Cytoplasmic HSPB1/t expression levels decreased significantly following cisplatin therapy while nuclear HSPB1/t and HSPB1/p tended to increase. Since the most significant changes following chemotherapy appeared in the HSPB1 expression levels, the changes were confirmed by western blot. The platinumDNA adducts were observed in HeLa cell in apoptosis, however in the tumor samples the platinum-DNA adducts were observed in morphologically healthy tumor cells, these cells displayed nuclear HSPB1/p. Further mechanistic studies should be performed to reveal how HSPB1/p is related with drug resistance. When the correlations of the markers with the response to neoadjuvant chemotherapy were examined, only high pre-chemotherapy levels of cytoplasmic HSPB1/p correlated with a poor clinical and pathological response to neodjuvant cisplatin chemotherapy (p=0.056) suggesting that this marker could be useful opening its study in a larger number of cases.