| Background: To explore the role of HO-1and its molecular mechanismin chemotherapy resistance of androgen-independent prostate cancer.Prostate cancer (PCa), is the most commonly diagnosed cancer and thesecond leading cause of cancer-related death in men in western developedcountries (1,2). Almost all prostate cancer patients receiving androgendeprivation therapy (ADT) after18-24months develop hormone-refractoryprostate cancer (HRPC), which is highly metastatic and has poor prognosis.Although the use of various anticancer drugs to relief pain, there was nosignificant advantage in survival, but also nearly insensitive to standardradiation and chemotherapeutic treatments (3).Chemoresistance represents themain obstacle in the treatment of prostate cancer and improving the survivaland quality of life in patients with advanced prostate cancer. Therefore, it isvery important to detect the key molecular target and to develop novaltherapeutic strategies for resistance of HRPC to chemotherapy.Heme oxygenase-1(HO-1) is one of the powerful cytoprotectiveenzymes, which represents a prime cellular defense mechanism againstoxidative stress through its catalytic products such as ferrous iron, carbonmonoxide (CO) and biliverdin (5). It is induced by various stimuli such ashypoxia, heavy metals, chemotherapeutic drugs and oxidative stress. HO-1plays critical roles in antioxidant defense, anti-inflammatory andanti-apoptotic effect (6). Recently, some studys suggested that endogenousHO-1is usually higher expressed in neoplastic cells than in surroundinghealthy tissues, such as squamous carcinoma (7), melanoma (8), glioblastoma(9), lymphosarcoma (10), and siRNA-mediated knockdown of HO-1couldsuppress the growth of bladder cancer cells (12), suggesting HO-1is described as a protumoral molecule because of its cytoprotective action. Even moreimportant, HO-1prevents cancer cells from chemotherapeutic agents-inducedapoptosis, and targeted knockdown of HO-1gene expression or suppression ofHO-1activity in vitro significantly enhance the chemosensitivity of cancercells (13,14). Under oxidative stress environment caused by chemotherapeuticagents, cancer cells maybe upregulateantioxidant defenses and enhance anti-apoptotic capacity to resistant tooxidative injury induced by anticancer agents (15), which is possiblely a majorcause of chemoresistance, but poor data identified it and its mechanism is notclear till now. As a powerful anti-apoptotic and antioxidant enzyme, inhibitionof HO-1would seem to be a logical approach to enhancing the therapeuticpotential of anticancer agents. However, the exact mechanism by whichsuppression of HO-1sensitize the anticancer effect of chemotherapeuticagents is largely unknown.Methods: PC-3cells were randomly divided into normal control group,Znpp group, Hemin group, Docetaxel group, Docetaxel+Znpp group, Docetaxel+Hemin group.1The expression of HO-1, BCL-2, Bax protein by Immunohistochemicalanalysis.2Cell viability in all experimental groups by MTT.3Reactive oxygen species (ROS) levels by DCFH-DA method.4Apoptosis rate by TUNEL assay.5he expression of HO-1, Bcl-2, Bax, caspase-3, caspase-9andcytochrome C by Western blot.Results:1Association of HO-1immunohistochemical expression with clinico-pathological characteristics of prostatic carcinomas.The results showed that there was a trend toward an association betweenincreased HO-1and higher clinical stage, higher pre-operative PSA levels,positive seminal vesicle invasion and higher Gleason grades，HO-1expressionshowed no statistical correlation to patient age, lymph node metastasis, urethral invasion.2Correlation between HO-1and apoptosis-related preteins Bcl-2andBax immunohistochemical expression in samples of primary prostate cancer.We found that there is a direct correlation between HO-1expression andBax or Bcl-2expression in prostate cancer samples, the trend was clearlydetected toward higher levels of HO-1expression with increasing Bcl-2expression and decreasing Bax expression.3Effects of Hemin and Znpp on Docetaxel-induced cytotoxicity in PC-3cell by MTT.4Enhanced cellular apoptosis of PC-3cells induced by Docetaxel afterHO-1inhibition.5Docetaxel induce generation of ROS and inhibition of HO-1expression increase ROS generation induced by Docetaxel in PC-3cell.6Docetaxel induced-ROS generation up-regulate Bax anddown-regulate Bcl-2expression and HO-1reversed those effects.7Inhibition of HO-1expression potentiates Docetaxel-inducedmitochondria-dependent apoptotic pathway in PC-3cell.Conclusion: Overexpression of HO-1is assistant to the progression ofprostatecancer, and it participates in anti-apoptosis through up-regulationBcl-2or down-regulation Bax expression. Inhibition of heme oxygenase-1enhances Docetaxel-induced PC-3cells apoptosis via ROS generation andmitochondria apoptosis pathway. |
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