| Background: Cervical cancer is one of the most common malignancies in women, and itsincidence is a leading one in the malignant cancer in women, second only to breast cancer. Cervical cancerhas an increasing incidence and mortality and the age of onset becomes younger year by year in China.Consequently, cervical cancer is becoming a serious threat to women’s health in China. Currently, surgeryand chemotherapy remain the preferred approaches to treat cervical cancer. Chemoresistance is one of thekey reasons for the poor efficacy of chemotherapy and poor prognosis of the patients with cervical cancer.Nevertheless, the precise mechanism about chemoresistance of cervical cancer is not completelyunderstood.Chemotherapeutics, such as doxorubicin, inhibit the proliferation or promote the apoptosis oftumor cells, by inducing the activation of tumor suppressor gene p53and subsequently triggering theexpression of p53downstream target genes. Phosphorylation, ubiquitination and other post-translationalmodifications of p53are critical for the biological activity of p53. Acetylation of p53enhances the stabilityof p53and promote p53transcriptional activity. The acetylation of P53is a reversible reaction. SIRT1, ahistone deacetylase, inhibits p53transcriptional activity and the expression of downstream target genes ofp53, by catalyzing deacetylation of P53,Psychological stress, which often induce a chronic stress response, is very prevalent amongcancer patients. Mounting evidence proved that chronic stress response exerted remarkable effects on themalignant progression of cancer and the prognosis of patients. In our previous study, we proved thatglucocorticoid, one of most important stress-related hormone, induced the resistance of cervical cancercells to chemotheraputics treatment, through inhibiting p53and miR-145levels by enhancing HPV E6expression. The data suggested that the stress-related hormones might play an important role in themalignant progression of cancer induced by chronic stress response.Catecholamines (epinephrine and norepinephrine) are another type of important stress–relatedhormones. Levels of catecholamines are continually increased in individuals who experience chronic stress.Previous studies by us and other groups proved that catecholamine play an important role in the regulationof the biological behaviors of the tumor cells. However, whether catecholamine exert affects on thesensitivity of cervical cancer cells to chemotheraputics remain unexplored and the underlying molecularmechanisms are unclear.Objective: The aim of this study is to explore the effects exerted by catecholamine on thesensitivities of cervical cancer cells to chemotheraputics, as well as try to elucidate the precise mechanismunderlying this process.Methods:(1) Evaluating the expression of SIRT1in cervical cancer cells in response tocatecholamine stimulation by Western-Blot assay;(2) RT-PCR was employed to detecte the expression ofSIRT1at transcriptional level in cervical cancer cells in response to catecholamine stimulation;(3)Western-Blot and Immunol fluorescence assays were used to explore the effect of catecholamine and chemotheraputics on p53acetylation and SIRT1expression;(4) Dual luciferase reporter gene assay wasemployed to detect the effect of catecholamine on doxorubicin-induced p53transcriptional activity;(5)Apoptosis assays were used to evaluate the role of catecholamine in doxorubicin-induced apoptosis ofcervical cancer cells;(6) The effects of catecholamine on the sensitivity of cervical cancer cells tochemotheraputics were explored by the cell proliferation assay;(7) Western-Blot and dual luciferasereporter gene assays were employed to detect the role of SIRT1in doxorubicin-induced P53acetylation andp53transcriptional activity;(8) Catecholamine-induced chemoresistance in cervical cancer cells wasevaluated by in vivo assay;(9) Immunohistochemistry assay was used to evaluate the expression of β2-ARin cervical cancer tissue samples.Result:(1) The expression of SIRT1was evidently upregulated by catecholamine stimulationin cervical cancer cells in time and dose-dependent manners.(2) Catecholamine stimulation significantlyup-regulated the expression of SIRT1at the transcriptional level.(3) Catecholamine inhibited the level ofP53acetylation induced by chemotherapy drug.(4) Catecholamine significantly repressed p53transcriptional activity induced by doxorubicin.(5) Catecholamine inhibited the apoptosis of cervicalcancer cells induced by doxorubicin.(6) Catecholamine greatly antagonized doxorubicin-inducedinhibitory effect on the proliferation of cervical cancer cells.(7) SIRT1playe a key role in thecatecholamine-induced inhibition of p53acetylation and p53transcriptional activity.(8) Catecholamineinhibited the efficacy of doxorubicin in vivo.(9) High level of β2-AR was found in some cervical cancertissue samples.Conclusion: In this study, we found that catecholamine antagonized the effects ofchemotheraputics on the proliferation and apoptosis of cervical cancer cells in vitro and in vivo, bymanipulating β2-AR-SIRT1-P53pathway. In addition, high level of β2-AR expression was found in somecervical cancer tissue samples, implying the critical of catecholamine in the malignant progression ofcervical cancer. The further exploration of this study may contribute to improving the efficacy ofchemotheraputics in clinical practice. |
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