Cell-cycle dysregulation and the molecular mechanisms of prostate cancer

Amanatullah, Derek F.; Reutens, Anne T.; Zafonte, Brian T.; Fu, Maofu; Mani, Sridhar; Pestell, Richard G.

doi:10.2741/amanatullah

Cited by 46 publications

(24 citation statements)

References 148 publications

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“…Androgen-insensitive prostate cancer cells are characterized by increased growth, adhesion, invasion and migration [1][2][3][4]. We show here that an interaction between the AR and the EGFR at the membrane level occurs in androgen-sensitive prostate cancer cell lines and show evidence that the reduced invasive properties of these cells are due to an interaction between the EGFR and AR, decreased signalling leading to EGFR autotransphosphorylation and lower PI3K activation in response to EGF.…”

Section: Discussionmentioning

confidence: 76%

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The androgen receptor associates with the epidermal growth factor receptor in androgen-sensitive prostate cancer cells

et al. 2004

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Many recent evidences indicate that androgen-sensitive prostate cancer cells have a lower malignant phenotype that is in particular characterized by a reduced migration and invasion. We previously demonstrated that expression of androgen receptor (AR) by transfection of the androgen-independent prostate cancer cell line PC3 decreases invasion and adhesion of these cells (PC3-AR) through modulation of ␣6␤4 integrin expression. The treatment with the synthetic androgen R1881 further reduced invasion of the cells without, however, modifying ␣6␤4 expression on the cell surface, suggesting an interference with the invasion process in response to EGF. We investigated whether the presence of the AR could affect EGF receptor (EGFR)-mediated signaling in response to EGF by evaluating autotransphosphorylation of the receptor as well as activation of downstream signalling pathways. Immunoprecipitation studies demonstrated a reduction of EGF-induced tyrosine phosphorylation of EGFR in PC3-AR cells. In addition, EGF-stimulated PI3K activity, a key signalling pathway for invasion of these cells, was decreased in PC3-AR cells and further reduced by treatment with R1881, indicating decreased functionality of EGFR. An interaction between EGFR and AR has been demonstrated by immunoconfocal and co-immunoprecipitation analysis in PC3-AR cells, suggesting a possible interference of AR on EGFR signalling by interaction of the two proteins. In conclusion, our results suggest that the expression of AR by transfection in PC3 cells confers a less malignant phenotype by interfering with EGFR autophosphorylation and signalling in response to EGF leading to invasion through a mechanism involving an interaction between AR and EGFR.

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Section: Discussionmentioning

confidence: 76%

“…Prostate cancer (PC) is the most common malignancy detected in men in western countries [1,2]. Although endocrine therapy is very useful when surgery is not feasible and leads to substantial periods of remission, progression from androgen dependence to independence always occurs in treated patients.…”

Section: Introductionmentioning

confidence: 99%

The androgen receptor associates with the epidermal growth factor receptor in androgen-sensitive prostate cancer cells

et al. 2004

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“…Prostate cancer is the most frequently diagnosed cancer in western males [35]. The progression of most of the cancers including prostate cancer may be a result of defects in cell cycle and apoptotic machinery.…”

Section: Discussionmentioning

confidence: 99%

<i>In Vitro</i> Anticancer Activity of Plant-Derived Cannabidiol on Prostate Cancer Cell Lines

Sharma¹,

Hudson²,

Adomat³

et al. 2014

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Cannabinoids, the active components of Cannabis sativa Linnaeus, have received renewed interest in recent years due to their diverse pharmacologic activities such as cell growth inhibition, anti-inflammatory effects and tumor regression, but their use in chemotherapy is limited by their psychotropic activity. To date, cannabinoids have been successfully used in the treatment of nausea and vomiting, two common side effects that accompany chemotherapy in cancer patients. Most non-THC plant cannabinoids e.g. cannabidiol and cannabigerol, seem to be devoid of psychotropic properties. However, the precise pathways through which these molecules produce an antitumor effect have not yet been fully characterized. We therefore investigated the antitumor and anti-inflammatory activities of cannabidiol (CBD) in human prostate cancer cell lines LNCaP, DU145, PC3, and assessed whether there is any advantage in using cannabis extracts enriched in cannabidiol and low in THC. Results obtained in a panel of prostate cancer cell lines clearly indicate that cannabidiol is a potent inhibitor of cancer cell growth, with significantly lower potency in non-cancer cells. The mRNA expression level of cannabinoid receptors CB1 and CB2, vascular endothelial growth factor (VEGF), PSA (prostate specific antigen) are significantly higher in human prostate cell lines. Treatment with Cannabis extract containing high CBD down regulates CB1, CB2, VEGF, PSA, pro-inflammatory cytokines/chemokine IL-6/IL-8. Our overall findings support the concept that cannabidiol, which lacks psychotropic activity, may possess anti-inflammatory property and down regulates both cannabinoid receptors, PSA, VEGF, IL-6 and IL-8. High CBD cannabis extracts are cytotoxic to androgen responsive LNCaP cells and may effectively inhibit spheroid formation in cancer stem cells. This activity may contribute to its anticancer and chemosensitizing effect against prostate cancer. Cannabidiol and other non-habit forming cannabinoids could be used as novel therapeutic agents for the treatment of prostate cancer.

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“…1 Since prostate cancer cell growth is enhanced by androgens, in the advanced stages of the disease, androgen ablation therapy represents a valuable tool for the treatment of these patients. However the development in most patients after few years of treatment of androgenindependent clones, characterized by higher invasiveness and metastatic properties, has focused attention on the molecular mechanisms that lead to loss of androgen-dependence as well as on the pathways that are regulated by androgens in these cells besides proliferation.…”

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confidence: 99%

EGF receptor (EGFR) signaling promoting invasion is disrupted in androgen‐sensitive prostate cancer cells by an interaction between EGFR and androgen receptor (AR)

Bonaccorsi

Carloni

Muratori

et al. 2004

Intl Journal of Cancer

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We previously demonstrated that expression of androgen receptor (AR) by transfection of the androgen-independent prostate cancer cell line PC3 decreases invasion and adhesion of these cells (PC3-AR) through modulation of ␣6␤4 integrin expression. The treatment with androgens further reduced invasion of the cells without modifying ␣6␤4 expression, suggesting an interference with the invasion process by androgens. Here, we investigated EGF-mediated signal transduction processes that lead to invasion in PC3-AR cells. We show that EGF-induced EGFR autotransphosphorylation is reduced in PC3-AR cells compared to PC3 cells transfected only with the vector (PC3-Neo). EGF-stimulated PI3K activity, a key signaling pathway for invasion of these cells, and EGF-PI3K interaction are also decreased in PC3 Key words: prostate cancer; epidermal growth factor receptor; androgen receptor; PI3K; invasionProstate Cancer (PC) is one of the most common cancer and the second leading cause of death in American men. 1 Since prostate cancer cell growth is enhanced by androgens, in the advanced stages of the disease, androgen ablation therapy represents a valuable tool for the treatment of these patients. However the development in most patients after few years of treatment of androgenindependent clones, characterized by higher invasiveness and metastatic properties, has focused attention on the molecular mechanisms that lead to loss of androgen-dependence as well as on the pathways that are regulated by androgens in these cells besides proliferation. Indeed, although androgens are the major stimulus for proliferation of prostate cancer cells, maintenance of androgensensitivity appears to keep a more differentiated and less malignant phenotype of these cells. The ability to produce tumors in nude mice, for instance, is higher in androgen-insensitive cell lines (such as PC3 and DU145) with respect to androgen sensitive (LNCaP). 2 In this light, the role of androgens in the regulation of the pathways involved in invasion and metastasis represents a major task in studies on prostate cancer biology. 3 As a result, some androgen-regulated genes involved in signaling pathways that lead to invasion have been recently identified 4 -6 and their role in decreasing invasion ability of androgen-sensitive prostate cancer cells indicated. Migration and invasion of cancer cells is regulated by multiple pathways that employ various growth factor and their receptors, integrins and cytoskeletal elements. A key role is played by the EGF receptor (EGFR), which, following interaction with the integrin ␣6␤4, promotes cell migration through activation of PI3K and other downstream pathways. 7,8 In a previous study, we demonstrated that the expression of androgen receptor in PC3 cells by transfection with a full-length human androgen receptor expression vector (PC3-AR) determined a decrease in the expression of the integrin ␣6␤4 and in the ability of these cells to invade Matrigel in response to EGF. 6 The treatment with the synthetic androgen R1881 determined a ...

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Cell-cycle dysregulation and the molecular mechanisms of prostate cancer

Cited by 46 publications

References 148 publications

The androgen receptor associates with the epidermal growth factor receptor in androgen-sensitive prostate cancer cells

The androgen receptor associates with the epidermal growth factor receptor in androgen-sensitive prostate cancer cells

<i>In Vitro</i> Anticancer Activity of Plant-Derived Cannabidiol on Prostate Cancer Cell Lines

EGF receptor (EGFR) signaling promoting invasion is disrupted in androgen‐sensitive prostate cancer cells by an interaction between EGFR and androgen receptor (AR)

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Cell-cycle dysregulation and the molecular mechanisms of prostate cancer

Cited by 46 publications

References 148 publications

The androgen receptor associates with the epidermal growth factor receptor in androgen-sensitive prostate cancer cells

The androgen receptor associates with the epidermal growth factor receptor in androgen-sensitive prostate cancer cells

&lt;i&gt;In Vitro&lt;/i&gt; Anticancer Activity of Plant-Derived Cannabidiol on Prostate Cancer Cell Lines

EGF receptor (EGFR) signaling promoting invasion is disrupted in androgen‐sensitive prostate cancer cells by an interaction between EGFR and androgen receptor (AR)

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<i>In Vitro</i> Anticancer Activity of Plant-Derived Cannabidiol on Prostate Cancer Cell Lines