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.
    Asian Pacific journal of cancer prevention: APJCP 05/2014; 15(12):20-28. DOI:10.7314/APJCP.2014.15.12.5043 · 2.51 Impact Factor
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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.
    International Journal of Endocrinology 03/2014; 2014:470592. DOI:10.1155/2014/470592 · 1.95 Impact Factor
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    • "However, in this study, we found that luteoloside had no significantly effect on the protein levels of LC3 and Beclin 1 (Figure S2), two important autophagy markers. The new classification of cell death established by the Nomenclature Committee on Cell Death (NCCD) was based on molecular features [46], [47]. According to this classification, cell deaths can be roughly divided into: apoptosis (caspase dependent extrinsic apoptosis and caspase-independent intrinsic apoptosis), necrosis, autophagy cell death, and other tentative definitions of cell death modalities including anoikis, entosis, pyroptosis, netosis and cornification. "
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    ABSTRACT: The inflammasome is a multi-protein complex which when activated regulates caspase-1 activation and IL-1β secretion. Inflammasome activation is mediated by NLR proteins that respond to stimuli. Among NLRs, NLRP3 senses the widest array of stimuli. NLRP3 inflammasome plays an important role in the development of many cancer types. However, Whether NLRP3 inflammasome plays an important role in the process of hepatocellular carcinoma (HCC) is still unknown. Here, the anticancer effect of luteoloside, a naturally occurring flavonoid isolated from the medicinal plant Gentiana macrophylla, against HCC cells and the underlying mechanisms were investigated. Luteoloside significantly inhibited the proliferation of HCC cells in vitro and in vivo. Live-cell imaging and transwell assays showed that the migration and invasive capacities of HCC cells, which were treated with luteoloside, were significantly inhibited compared with the control cells. The inhibitory effect of luteoloside on metastasis was also observed in vivo in male BALB/c-nu/nu mouse lung metastasis model. Further studies showed that luteoloside could significantly reduce the intracellular reactive oxygen species (ROS) accumulation. The decreased levels of ROS induced by luteoloside was accompanied by decrease in expression of NLRP3 inflammasome resulting in decrease in proteolytic cleavage of caspase-1. Inactivation of caspase-1 by luteoloside resulted in inhibition of IL-1β. Thus, luteoloside exerts its inhibitory effect on proliferation, invasion and metastasis of HCC cells through inhibition of NLRP3 inflammasome. Our results indicate that luteoloside can be a potential therapeutic agent not only as an adjuvant therapy for HCC, but also, in the control and prevention of metastatic HCC.
    PLoS ONE 02/2014; 9(2):e89961. DOI:10.1371/journal.pone.0089961 · 3.23 Impact Factor
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