Abstract
Cervical cancers/CCs are one of the commonest malignancies and the second leading cause of cancer-related death in women. Resveratrol inhibits CC cell growth but its molecular target(s) remains unclear. Since the signaling pathways mediated by STAT3, Notch1 and Wnt2 play beneficial roles in CC formation and progression, the effects of resveratrol on them in cervical adenocarcinoma (HeLa) and squamous cell carcinoma (SiHa) cells were analyzed. The biological significances of the above signaling for HeLa and SiHa cells were evaluated by treating the cells with STAT3, Wnt or Notch selective inhibitors. The frequencies of STAT3, Notch and Wnt activations in 68 cases of CC specimens and 38 non-cancerous cervical epithelia were examined by tissue microarray-based immunohistochemical staining. The results revealed that HeLa and SiHa cells treated by 100μM resveratrol showed extensive apoptosis, accompanied with suppression of STAT3, Notch and Wnt activations. Growth inhibition and apoptosis were found in HeLa and SiHa populations treated by AG490, a STAT3/JAK3 inhibitor but not the ones treated by Notch inhibitor L-685,458 or by Wnt inhibitor XAV-939. Immunohistochemical staining performed on the tissue microarrays showed that the frequencies of Notch1, Notch2, Hes1, Wnt2, Wnt5a and p-STAT3 detection as well as β-catenin nuclear translocation in CC samples were significantly higher than that of noncancerous group (p<0.01), while the expression rate of PIAS3 was remarkably low in cancer samples (p<0.01). Our results thus demonstrate that STAT3, Wnt and Notch signaling are frequently co-activated in human CC cells and specimens and resveratrol can concurrently inhibit those signaling activations and meanwhile lead cervical squamous cell carcinoma and adenocarcinoma cells to growth arrest and apoptosis. STAT3 signaling is more critical for CC cells and is the major target of resveratrol because selective inhibition of STAT3 rather than Wnt or Notch activation commits SiHa and HeLa cells to apoptosis.
Highlights
Cervical cancers (CC) are one of the leading causes of cancer-related death among women in developing countries [1, 2], which are classified into squamous cell carcinomas and adenocarcinomas according to their cellular origins [3]
Predominant nuclear labelling of Hes1, β-catenin and p-STAT3 were found in normally cultured HeLa and SiHa cells, which became weakened by resveratrol
Paralleled Reverse transcription (RT)-polymerase chain reaction (PCR) and Western blot analyses showed that Notch1, Notch2, Hes1, Wnt2, Wnt5a and β-catenin were obviously downregulated and protein inhibitor of activated STAT3 (PIAS3) was up-regulated in resveratroltreated HeLa and SiHa cells (Figure 2A and 2B; p
Summary
Cervical cancers (CC) are one of the leading causes of cancer-related death among women in developing countries [1, 2], which are classified into squamous cell carcinomas and adenocarcinomas according to their cellular origins [3]. It is of clinical values to explore more reliable and less toxic therapeutic approach in the adjuvant treatment of cervical cancers. Human medulloblastoma cells are sensitive to resveratrol in terms of growth arrest, neuron-oriented differentiation and distinct apoptosis [11]. The growth of transplanted human transitional cell carcinomas in nude mouse urinary bladders can be efficiently suppressed by regular resveratrol installation [12]. Resveratrol has little harmful effect on glial cells and neurons in central nervous system and the tumor surrounding uroepithelium [13, 14], suggesting its potential values in the clinical treatments of those cancers. In the case of cervical cancers, resveratrol exerts radiosensitizing and anti-proliferative effects on them [15], but its underlying molecular mechanism remains to be investigated
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