142 The role of hypoxia, p53, and apoptosis in human cervical carcinoma pathogenesis

Kim, Charlotte Y.; Tsai, Mitchell H.; Osmanian, Cynthia; Calkins, Dennise P.; Graeber, Thomas G.; Greenspan, David L.; Kennedy, Andrew S.; Rinker, Lillian H.; Varia, Mahesh A.; DiPaolo, Joseph A.; Peehl, Donna M.; Raleigh, James A.; Giaccia, Amato J.

doi:10.1016/s0360-3016(97)80701-8

Cited by 12 publications

(11 citation statements)

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“…This was supported by our observation that induction of apoptosis by overexpression of E2F-1 directly induced IL-1a release. Current results are consistent with observations that the HPV-16 E7 or E6/E7 proteins enhance apoptosis in a variety of cell types (Kim et al, 1997;Pan and Griep, 1995;Puthenveettil et al, 1996;Rorke and Jacobberger, 1995) and that apoptosis of macrophages results in release of biologically active IL-1a (Hogquist et al, 1991). In vitro results using retrovirus-infected keratinocytes were consistent with observations on cervical biopsies.…”

Section: Discussionsupporting

confidence: 90%

Human papillomavirus type 16 E7 protein sensitizes cervical keratinocytes to apoptosis and release of interleukin-1α

et al. 1998

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Interleukin-1a (IL-1a) is a multifunctional cytokine that promotes in¯ammation, tissue remodeling and epithelial hyperplasia. Keratinocytes produce and sequester large amounts of biologically active IL-1a which can be released after injury or infection. We show that high level expression of human papillomavirus (HPV) type 16 E6 and E7 oncoproteins enhanced release of IL-1a from cultures of normal cervical keratinocytes (relative eectiveness E74E6/E7>E64 control). The amount of IL-1a released was directly related to the ability of E7 or E6/E7 to stimulate apoptosis. E7 proteins that bound the retinoblastoma protein (Rb) strongly (HPV-16 and -18) induced more IL-1a release than those that bound poorly (HPV-6 and an HPV-16 E7 24gly mutant). Furthermore, overexpression of the E2F-1 transcription factor, a downstream target of Rb, induced extensive apoptosis and IL-1a release. Apoptosis and IL-1a release in response to growth factor removal occurred in part through a p53-independent pathway as coexpression of E6 and downregulation of p53 did not prevent either response. Immunohistochemical analyses showed that IL1a was expressed by keratinocytes in normal cervical epithelia, low and high grade dysplasias, and cervical carcinomas. However, HPV-16 E6/E7 RNA expression and apoptosis increased in parallel in proliferating keratinocytes in severe dysplasias and carcinomas suggesting that IL-1a release is associated with progression to high grade disease. Thus, high level expression of the HPV-16 E7 protein sensitizes keratinocytes to apoptosis which results in release of IL-1a.

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Section: Discussionsupporting

confidence: 90%

Human papillomavirus type 16 E7 protein sensitizes cervical keratinocytes to apoptosis and release of interleukin-1α

et al. 1998

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“…It would be of interest to note that as the rounds of selection proceeded A11 cells progressively became more resistant to apoptosis induced by not only hypoxia but also serum starvation, glucose deprivation and anticancer drugs such as cisplatin and etoposide (not shown). Therefore, it is likely that repeated exposure to hypoxia-reoxygenation results in the selection of not merely A11 cells with original phenotype but of A11 cells with more malignant phenotype, consistent with previous reports (Kim et al, 1997;Kinoshita et al, 2001).…”

Section: Discussionsupporting

confidence: 90%

Hypoxia selects for high-metastatic Lewis lung carcinoma cells overexpressing Mcl-1 and exhibiting reduced apoptotic potential in solid tumors

et al. 2005

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Low oxygen tension (hypoxia) is a common feature of solid tumors and stimulates the expressions of a variety of genes including those related to angiogenesis, apoptosis and endoplasmic reticulum (ER) stress response. Here we show a close correlation between metastatic potential and the resistance to hypoxia-and ER stress-induced apoptosis among the cell lines with differing metastatic potential derived from Lewis lung carcinoma. An apoptosis-specific expression profiling and immunoblot analyses revealed that the expression of antiapoptotic Mcl-1 increased as the resistance to apoptosis increased. Downregulation of the Mcl-1 expression in the high-metastatic cells by Mcl-1 small interfering RNA increased the sensitivity to hypoxia-induced apoptosis and decreased the metastatic ability. The hypoxia-induced apoptosis was not associated with p53 accumulation, although at present it is not possible to conclude that apoptosis-induced apoptosis is p53-independent. There was no correlation between the expression levels of ER stress-response proteins GADD153, GRP78 and ORP150 and the resistance to hypoxia or ER stresses. In vitro, small numbers of the high-metastatic cells overtook the low-metastatic cells after exposure to several rounds of hypoxia and reoxygenation. In solid tumors initially established from equal mixtures, the proportion of the high-metastatic cells to low-metastatic cells was significantly higher in hypoxic areas. Moreover, the high-metastatic cells were overtaking the low-metastatic cells in some of the tumors. Thus, tumor hypoxia and ER stress may provide a physiological selective pressure for the expansion of the high-metastatic cells overexpressing Mcl-1 and exhibiting reduced apoptotic potential in solid tumors.

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“…It has been shown that in vitro modelling of this in vivo situation by repeated exposure to conditions of severe hypoxia induces apoptosis and selects for cells with defects in relevant apoptotic pathways (Graeber et al, 1996;Kim et al, 1997). Our observations regarding the significance of the intrinsic pathway for hypoxiainduced apoptosis suggest that a selection pressure may be mainly exerted on elements of this signaling cascade.…”

Section: Discussionmentioning

confidence: 67%

Molecular ordering of hypoxia-induced apoptosis: critical involvement of the mitochondrial death pathway in a FADD/caspase-8 independent manner

et al. 2004

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142 The role of hypoxia, p53, and apoptosis in human cervical carcinoma pathogenesis

Cited by 12 publications

References 0 publications

Human papillomavirus type 16 E7 protein sensitizes cervical keratinocytes to apoptosis and release of interleukin-1α

Human papillomavirus type 16 E7 protein sensitizes cervical keratinocytes to apoptosis and release of interleukin-1α

Hypoxia selects for high-metastatic Lewis lung carcinoma cells overexpressing Mcl-1 and exhibiting reduced apoptotic potential in solid tumors

Molecular ordering of hypoxia-induced apoptosis: critical involvement of the mitochondrial death pathway in a FADD/caspase-8 independent manner

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