Inorganic Arsenite-Induced Malignant Transformation of Human Prostate Epithelial Cells

Achanzar, William E.; Brambila, Eduardo; Diwan, Bhalchandra A.; Webber, Mukta M.; Waalkes, Michael P.

doi:10.1093/jnci/94.24.1888

Cited by 196 publications

(311 citation statements)

References 17 publications

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“…Low-level, chronic arsenic exposure can induce malignant transformation in various human and rodent cells [28][29][30][31][32]. In the present study when HaCaT cells were continuously exposed to environmentally relevant levels of arsenic for a protracted period, malignant transformation occurred as evidenced by the formation of highly aggressive SCC, a common form of skin cancer in arsenic-exposed humans [1], after inoculation of nude mice.…”

Section: Discussionmentioning

confidence: 92%

“…MMP-9 specifically targets type IV collagen, a major component of basement membrane, and appears to play a crucial role in tumor invasion across the basement membrane [34]. Elevated expression levels of MMP-9 are strongly correlated with malignant phenotype in SCC [34] and are characteristic of malignant transformation of cells [29]. In human keratinocyes constitutive production and secretion of MMP-9 correlate with the degree of tumorigenicity in malignantly transformed clones [33].…”

Section: Discussionmentioning

confidence: 99%

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Arsenic-induced malignant transformation of human keratinocytes: Involvement of Nrf2

Diwan

Sun

et al. 2008

Free Radical Biology and Medicine

158

147

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Arsenic is a well-known human skin carcinogen but the underlying mechanisms of carcinogenesis are unclear. Transcription factor Nrf2-mediated antioxidant response represents a critical cellular defense mechanism, and emerging data suggest that constitutive activation of Nrf2 contributes to malignant phenotype. In the present study when an immortalized, non-tumorigenic human keratinocyte cell line (HaCaT) was continuously exposed to environmentally relevant level of inorganic arsenite (100 nM) for 28 weeks, malignant transformation occurred as evidenced by the formation of highly aggressive squamous cell carcinoma after inoculation into nude mice. To investigate the mechanisms involved, a broad array of biomarkers for transformation were assessed in these arsenic-transformed cells (termed As-TM). In addition to increased secretion of matrix metalloproteinase-9 (MMP-9), a set of markers for squamous differentiation and skin keratinization, including keratin-1, keratin-10, involucrin, and loricrin, were significantly elevated in As-TM cells. Furthermore, As-TM cells showed increased intracellular glutathione, elevated expression of Nrf2 and its target genes, as well as generalized apoptotic resistance. In contrast to increased basal Nrf2 activity in As-TM cells, a diminished Nrf2-mediated antioxidant response induced by acute exposure to high dose of arsenite or tert-butyl hydroxyquinone occurred. The findings that multiple biomarkers for malignant transformation observed in As-TM cells, including MMP-9 and cytokeratins, are potentially regulated by Nrf2 suggest constitutive Nrf2 activation may be involved in arsenic carcinogenesis of skin. The weakened Nrf2 activation in response to oxidative stressors observed in As-TM cells, coupled with acquired apoptotic resistance, would potentially have increased the likelihood of transmittable oxidative DNA damage and fixation of mutational/DNA damage events.

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Section: Discussionmentioning

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Arsenic-induced malignant transformation of human keratinocytes: Involvement of Nrf2

Diwan

Sun

et al. 2008

Free Radical Biology and Medicine

158

147

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“…After 48 h, the conditioned medium was collected and the MMP activity was analysed as described previously (Achanzar et al, 2001).…”

Section: Zymographic Analysis Of Mmp Activitymentioning

confidence: 99%

Chronic UVA irradiation of human HaCaT keratinocytes induces malignant transformation associated with acquired apoptotic resistance

Huang

et al. 2006

Oncogene

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Ultraviolet A (UVA, 315-400 nm), constituting about 95% of ultraviolet irradiation in natural sunlight, represents a major environmental challenge to the skin and is clearly associated with human skin cancer. It has proven difficult to show direct actions of UVA as a carcinogen in human cells. Here, we demonstrate that chronic UVA exposures at environmentally relevant doses in vitro can induce malignant transformation of human keratinocytes associated with acquired apoptotic resistance. As evidence of carcinogenic transformation, UVAlong-treated (24 J/cm 2 once/week for 18 weeks) HaCaT (ULTH) cells showed increased secretion of matrix metalloproteinase (MMP-9), overexpression of keratin 13, altered morphology and anchorage-independent growth. Malignant transformation was established by the production of aggressive squamous cell carcinomas after inoculation of ULTH cells into nude mice (NC r -nu). ULTH cells were resistant to apoptosis induced not only by UVA but also by UVB and arsenite, two other human skin carcinogens. ULTH cells also became resistant to apoptosis induced by etoposide, staurosporine and doxorubicin hydrochloride. Elevated phosphorylation of protein kinase B (PKB, also called AKT) and reduced expression of phosphatase and tensin homologue deleted on chromosome 10 (PTEN) were detected in ULTH cells. The resistance of ULTH cells to UVA-induced apoptosis was reversed by either inhibition of phosphatidylinositol 3-kinase (PI-3K) or adenovirus expression of PTEN or dominant negative AKT. These data indicate that UVA has carcinogenic potential in human keratinocytes and that the increased AKT signaling and decreased PTEN expression may contribute to this malignant transformation. Further comparisons between the transformed ULTH and control cells should lead to a better understanding of the mechanism of UVA carcinogenesis and may help identify biomarkers for UVA-induced skin malignancies.

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“…Although Cd is known as a human lung carcinogen [1], there is some evidence that it may be related to other cancers such as human prostate cancer [3][4][5], renal cell carcinoma [6,7], and breast cancer [8,9]. The human mammary gland is a controversial target site for Cd.…”

Section: Introductionmentioning

confidence: 99%

Cadmium concentration in biological media of breast cancer patients

Strumylaitė

Boguševičius

Abdrachmanovas

et al. 2010

Breast Cancer Res Treat

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The study aimed to determine and compare cadmium (Cd) concentration in different biological media of breast cancer and benign breast tumor patients. Methods Concentration of Cd was determined in breast tissue, urine and blood of 57 breast cancer and 51 benign tumor patients. Two samples of breast tissue from each patient, i.e. tumor and healthy tissue were taken for the analysis. Cd in biological media was determined by atomic absorption spectrometry (Perkin-Elmer, Zeeman 3030). Results The mean Cd concentration in breast cancer patients was 0.053 µg/g (95% CI=0.042-0.065) for tumor sample and 0.02 µg/g (95% CI=0.014-0.026) for healthy breast tissue sample (p<0.001). In benign tumor patients the figures were following: 0.037 µg/g (95% CI=0.023-0.051) and 0.032 µg/g (95% CI=0.018-0.047) (p>0.05). Cd content in malignant tumor significantly differed from that in benign tumor (p<0.01). Cancer patients with positive estrogenreceptors had significantly greater concentration of breast tissue Cd compared to patients with negative estrogenreceptors (p=0.035). Adjusted for creatinine Cd in urine was significantly higher in cancer patients than in controls (p<0.001). In cancer patients a positive Spearman's correlation was found between Cd in tumor and healthy breast tissue, blood (r=0.44 and r=0.39, respectively, p<0.01). Correlation between Cd in urine of cancer patients and number of cigarettes smoked during lifetime was suggestive (r=0.59, p=0.075). Conclusion The data obtained show higher concentration of cadmium in breast tumor and urine of cancer patients and support a possible relationship between cadmium and breast cancer.

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Inorganic Arsenite-Induced Malignant Transformation of Human Prostate Epithelial Cells

Cited by 196 publications

References 17 publications

Arsenic-induced malignant transformation of human keratinocytes: Involvement of Nrf2

Arsenic-induced malignant transformation of human keratinocytes: Involvement of Nrf2

Chronic UVA irradiation of human HaCaT keratinocytes induces malignant transformation associated with acquired apoptotic resistance

Cadmium concentration in biological media of breast cancer patients

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