Cadmium down-regulates expression of XIAP at the post-transcriptional level in prostate cancer cells through an NF-κB-independent, proteasome-mediated mechanism

Golovine, Konstantin; Makhov, Petr; Uzzo, Robert G.; Kutikov, Alexander; Kaplan, David J.; Fox, Eric; Kolenko, Vladimir

doi:10.1186/1476-4598-9-183

Cited by 29 publications

(13 citation statements)

References 58 publications

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“…While many studies have focussed upon differences in mRNA levels of these proteins there is also evidence for significant regulation of both at the protein level (10). Both XIAP (17) and survivin (18) have been shown as regulated through mechanisms controlling the proteasome degradation pathway. In addition there is evidence for other posttranslational mechanisms functioning to regulate these proteins (reviewed in refs.…”

Section: Discussionmentioning

confidence: 99%

Mechanisms of cisplatin-induced cell death in malignant mesothelioma cells: Role of inhibitor of apoptosis proteins (IAPs) and caspases

Cregan

Dharmarajan

Fox

2012

International Journal of Oncology

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Malignant mesothelioma (MM) is an aggressive and highly chemoresistant tumour. Although cisplatin is used in frontline therapy of this disease treatment remains palliative at best. The biochemical pathways activated by cisplatin and the mechanisms of resistance in mesothelioma cells are poorly understood. Overexpression of inhibitor of apoptosis proteins (IAPs) has been described in clinical mesothelioma tumours and proposed as therapeutic targets. In this study, we examined cisplatin-induced cell death pathways and IAPs in three mesothelioma-derived cell lines. Cisplatin induced cell death in mesothelioma cell lines was characterised by biochemical mechanisms classically associated with apoptosis including: mitochondrial depolarisation, phosphatidylserine translocation and caspase activation. Surprisingly mRNA expression of IAPs in mesothelioma was not upregulated relative to primary mesothelial cells except for survivin which was higher in the most resistant cell line. In contrast, protein expression of both XIAP and survivin was upregulated in all mesothelioma cells, consistent with post-translational regulation. Knockdown of either XIAP or survivin by RNAi did not affect the sensitivity to cisplatin in any of the cell lines. Survivin RNAi did, however, inhibit proliferation in the highest expressing cell line, ONE58. The pan-caspase inhibitor z-VAD and the more selective caspase 3/7 inhibitor z-DEVD had no effect upon the sensitivity of any of the cell lines to cisplatin indicating that caspase-independent pathways predominate. The findings of the present study provide insights into cisplatin-induced mechanisms in mesothelioma cells and show that alternative pathways are operating which may provide new options for targeting this extremely resistant tumour.

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Section: Discussionmentioning

confidence: 99%

Mechanisms of cisplatin-induced cell death in malignant mesothelioma cells: Role of inhibitor of apoptosis proteins (IAPs) and caspases

Cregan

Dharmarajan

Fox

2012

International Journal of Oncology

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“…Other reports link Cd exposure to genomic instability, aberrant gene expression, and inhibition of DNA damage repair and apoptosis through complex and multifactorial mechanisms [20,21]. Conversely though, Cd has also been shown to induce p53-dependent apoptosis [22] and down-regulation of the x-linked inhibitor of apoptosis protein (XIAP) in human prostate cancer cells [23]. Interestingly, synthetically made meclofenamic acid-Cd complexes have anti-proliferative activity in the breast cancer cell line MCF7, bladder cancer cell line T24, and the non-small cell lung carcinoma line A549 [24].…”

Section: Introductionmentioning

confidence: 99%

Organic cadmium complexes as proteasome inhibitors and apoptosis inducers in human breast cancer cells

Zhang

Buac

et al. 2013

Journal of Inorganic Biochemistry

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Although cadmium (Cd) is a widespread environmental contaminant and human carcinogen, our studies indicate an organic Cd complex to be a potent inhibitor of proteasomal chymotrypsin-like (CT-like) activity, further capable of inducing apoptosis in a cancer cell-specific manner. It has been reported that the ligands indole-3-butyric acid (L1) and indole-3-propionic acid (L2) have cancer-fighting effects when tested in a rat carcinoma model. In addition, 3, 5-diaminobenzoic acid o-vanillin Schiff bases (L3) have high antimicrobial activity and a large number of Schiff base complexes have been reported to have proteasome-inhibitory activity. We therefore hypothesized that synthetic forms of Cd in combination with L1, L2 and L3 may have proteasome-inhibitory and apoptosis-inducing activities, which would be cancer cell-specific. To test this hypothesis, we have synthesized three novel Cd-containing complexes: [Cd2(C12H12O2N)4(H2O)2]·2H2O (Cd1), [Cd2(C11H10O2N)4(H2O)2]·2H2O (Cd2) and [Cd(C7H4N2O2)(C8H6O2)2]·2H2O (Cd3), by using these three ligands. We sought out to characterize and assess the proteasome-inhibitory and anti-proliferative properties of these three Cd complexes in human breast cancer cells. Cd1, Cd2 and Cd3 were found to effectively inhibit the chymotrypsin-like activity of purified 20S proteasome with IC50 values of 2.6, 3.0 and 3.3 μM, respectively. Moreover, inhibition of cancer cell proliferation also correlated with this effect. As a result of proteasomal shutdown, the accumulation of ubiquitinated proteins and the proteasome target IκB-α protein as well as induction of apoptosis were observed. To account for the cancer specificity of this effect, immortalized, non-tumorigenic breast MCF10A cells were used under the same experimental conditions. Our results indicate that MCF10A cells are much less sensitive to the Cd1, Cd2 and Cd3 complexes when compared to MDA MB 231 breast cancer cells. Therefore, our study suggests that these Cd organic complexes are capable of inhibiting tumor cellular proteasome activity and consequently induce cancer cell-specific apoptotic death.

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“…Men with PCa have increased levels of cadmium both in the systemic circulation and prostatic tissues when compared with men that have a normal or hyperplastic prostate (Golovine et al, 2010; Habib et al, 1976; Lee et al, 2009; Ogunlewe and Osegbe, 1989). Epidemiologic evidence demonstrated a strong association between cadmium exposure and PCa in humans (Vinceti et al, 2007; Zeng et al, 2004.).…”

Section: Introductionmentioning

confidence: 99%

Early changes induced by short‐term low‐dose cadmium exposure in rat ventral and dorsolateral prostates

Lacorte

Delella

Amorim

et al. 2011

Microscopy Res & Technique

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Prostate cancer (PCa) is the most commonly diagnosed cancer in men. The etiology of PCa in humans is multifactorial and includes age, ethnicity, environmental factors, and other unknown causes. Epidemiological and experimental evidence has shown that cadmium is associated with PCa both in humans and rodents. This metal can act as an endocrine disruptor during prostate development, and it induces prostate lesions late in life. In this study, we investigated the effects of low-dose cadmium on rat prostate morphology during puberty. Two-month-old male Wistar rats were randomized into two experimental groups: cadmium-treated and control. The ventral and dorsolateral prostates were dissected, weighed, and immunohistochemically stained with specific antibodies against Ki-67 and the androgen receptor (AR). The concentration of cadmium was measured in the blood and prostate, and testosterone concentration was measured from the plasma. Our results show that cadmium concentration was increased in both the blood and the prostate of cadmium-treated rats, but there were no changes in the prostatic weight, epithelial cell height, or testosterone levels. However, AR immunostaining and epithelial cell proliferation (Ki-67 index) were increased in both prostates with an increase in apoptosis only in the dorsal lobe. Furthermore, atypical hyperplasic proliferative lesions were found in the dorsolateral lobe after cadmium exposure. Cadmium treatment reduced collagen fiber absolute volume in both prostates. Thus, low-doses of cadmium, even for a short period of time, can interfere with prostate epithelium-stroma homeostasis, and this disruption might be an important factor in the onset of prostate lesions late in life.

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Cadmium down-regulates expression of XIAP at the post-transcriptional level in prostate cancer cells through an NF-κB-independent, proteasome-mediated mechanism

Cited by 29 publications

References 58 publications

Mechanisms of cisplatin-induced cell death in malignant mesothelioma cells: Role of inhibitor of apoptosis proteins (IAPs) and caspases

Mechanisms of cisplatin-induced cell death in malignant mesothelioma cells: Role of inhibitor of apoptosis proteins (IAPs) and caspases

Organic cadmium complexes as proteasome inhibitors and apoptosis inducers in human breast cancer cells

Early changes induced by short‐term low‐dose cadmium exposure in rat ventral and dorsolateral prostates

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