Androgen receptor (AR) positive vs negative roles in prostate cancer cell deaths including apoptosis, anoikis, entosis, necrosis and autophagic cell death

George Whipple Lab for Cancer Research, Departments of Pathology and Urology, University of Rochester Medical Center, Rochester, NY 14642, USA.
Cancer Treatment Reviews (Impact Factor: 7.59). 08/2013; 40(1). DOI: 10.1016/j.ctrv.2013.07.008
Source: PubMed


Androgen/androgen receptor (AR) signaling plays pivotal roles in the prostate development and homeostasis as well as in the progression of prostate cancer (PCa). Androgen deprivation therapy (ADT) with anti-androgens remains as the main treatment for later stage PCa, and it has been shown to effectively suppress PCa growth during the first 12-24months. However, ADT eventually fails and tumors may re-grow and progress into the castration resistant stage. Recent reports revealed that AR might play complicated and even opposite roles in PCa progression that might depend on cell types and tumor stages. Importantly, AR may influence PCa progression via differential modulation of various cell deaths including apoptosis, anoikis, entosis, necrosis, and autophagic cell deaths. Targeting AR may induce PCa cell apoptosis, autophagic cell deaths and programmed necrosis, yet targeting AR may suppress cell deaths via anoikis and entosis that may potentially lead to increased metastasis. These differential functions of AR in various types of PCa cell death might challenge the current ADT with anti-androgens treatment. Further detailed dissection of molecular mechanisms by which AR modulates different PCa cell deaths will help us to develop a better therapy to battle PCa.

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    • "Using cell culture and detecting apoptosis are the best solutions to observe the response of cancer cells to drugs. Absence of apoptosis might cause uncontrolled cell proliferation and this is known as the characteristics of the cancer cells (Cooper and Hausman, 2006; Wang et al., 2014; Wen et al., 2014). Apoptosis emerges in both physiological and pathological conditions in organism and it is the selective removal processes of the cells which are dangerous for organism or cells are not require. "
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    ABSTRACT: Nowadays increasing effectiveness in cancer therapy and investigation of formation of new strategies that enhance antiproliferative activity against target organs has become a subject of interest. Although the molecular mechanisms of apoptosis can not be fully explained, it is known that cell suicide program existing in their memory genetically is activated by pathophysiological conditions and events such as oxidative stress. Low pressure (hypobaric) conditions that create hypoxia promote apoptosis by inhibiting cell cycling. In this study, determination of the effects of fractional hypobaric applications at different times on HeLa cells at cellular and molecular levels were targeted. Experiments were carried out under hypobaric conditions (35.2 kPa) in a specially designed hypobaric cabin including 2% O2 and 98% N. Application of fractional hypobaric conditions was repeated two times for 3 hours with an interval of 24 hours. At the end of the implementation period cells were allowed to incubate for 24 hours for activation of repair mechanisms. Cell kinetic parameters such as growth rate (MTT) and apoptotic index were used in determination of the effect of hypobaric conditions on HeLa cells. Also in our study expression levels of the Bcl-2 gene family that have regulatory roles in apoptosis were determined by the RT-PCR technique to evaluate molecular mechanisms. The results showed that antiproliferative effect of hypobaric conditions on HeLa cells started three hours from the time of application and increased depending on the period of exposure. While there was a significant decrease in growth rate values, there was a significant increase in apoptotic index values (p<0.01). Also molecular studies showed that hypobaric conditions caused a significant increase in expression level of proapoptotic gene Bax and significant decrease in antiapoptotic Bfl-1. Consequently fractional application of hypobaric conditions on HeLa cell cultures increased both antiproliferative and apoptotic effects and these effects were triggered by the Bax gene.
    Full-text · Article · May 2014 · Asian Pacific journal of cancer prevention: APJCP
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    • "So far, its exact pathogenesis and the reason of different prevalence among different races are not clear. Studies in recent years showed that the gene polymorphism of androgen receptor (AR), especially the polymorphism of repetitive sequence in CAG (the first exon), is closely related to the occurrence and development of prostate cancer [2] [3] [4] [5] . But most of the studies focused on the population in Europe and the United State where the risk of prostate cancer is high. "
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    ABSTRACT: Objective To explore the relation between the polymorphism of repetitive sequence in gene CAG of androgen receptor (AR) and the susceptibility and clinical stages as well as pathological grading of prostate cancer among Han population. Method Sixty-eight cases with prostate cancer hospitalized in Urinary Surgery Department from Feb. 2010 to Feb. 2012 and 60 healthy cases were chosen as research subjects. Methods of PCR and direct sequencing were adopted to detect DNA sequence of AR gene and the length of repetitive sequence in CAG. Results The lengths of repetitive sequence in CAG of patients with prostate cancer and healthy people were (22.3±4.6) and (23.0±4.9), respectively showing no statistical significance. Comparing length (repetitive sequence of CAG)>22, those with that < 22 suffer a remarkably higher risk of prostate cancer (P<0.05). The number of repetitive sequence in CAG of patients at clinical stage C-D was less than that of patients at stage B, and the number of repetitive sequence in CAG of patients with poorly differentiated prostate cancer was also less than that of patients with moderately and highly differentiated prostate cancer. But there was no statistical significance int the difference (P>0.05); the proportion of patients with length <22 at clinical stage C-D was much larger than that of patients at clinical stage B (P<0.05), and as the aggravation of pathological grading, the proportion of patients with the length <22 was also remarkably increased and there was significant difference between patients with highly differentiated prostate cancer and those with poorly differentiated prostate cancer (P<0.05). Conclusions There is correlation between the occurrence and development of prostate cancer in Han population and the polymorphism of repetitive sequence in gene CAG of androgen receptor. The less the number of repetitive sequence in CAG is, the higher the risk of prostate cancer will be and the more severe the clinical stage and pathological grading will be.
    Preview · Article · Apr 2014 · Asian Pacific Journal of Tropical Medicine
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    • "Finally, there is evidence in the literature that, in some instances, CRPCa may benefit from androgen-replacement therapies [43–45]. Overall, these studies suggest that AR may have both negative and positive roles in PCa progression by regulating cell growth and invasion ability [46, 47]. "
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    ABSTRACT: Prostate cancer (PCa) is the most common malignancy in elderly men. The progressive ageing of the world male population will further increase the need for tailored assessment and treatment of PCa patients. The determinant role of androgens and sexual hormones for PCa growth and progression has been established. However, several trials on androgens and PCa are recently focused on urinary continence, quality of life, and sexual function, suggesting a new point of view on the whole endocrinological aspect of PCa. During aging, metabolic syndrome, including diabetes, hypertension, dyslipidemia, and central obesity, can be associated with a chronic, low-grade inflammation of the prostate and with changes in the sex steroid pathways. These factors may affect both the carcinogenesis processes and treatment outcomes of PCa. Any treatment for PCa can have a long-lasting negative impact on quality of life and sexual health, which should be assessed by validated self-reported questionnaires. In particular, sexual health, urinary continence, and bowel function can be worsened after prostatectomy, radiotherapy, or hormone treatment, mostly in the elderly population. In the present review we summarized the current knowledge on the role of hormones, metabolic features, and primary treatments for PCa on the quality of life and sexual health of elderly Pca survivors.
    Full-text · Article · Mar 2014 · International Journal of Endocrinology
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