Less death in the dying

Polyák, Kornélia; Wu, Tsung Teh; Hamilton, Stanley R.; Kinzler, Kenneth W.; Vogelstein, Bert

doi:10.1038/sj.cdd.4400226

Cited by 21 publications

(16 citation statements)

References 14 publications

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“…This was seen clearly in the breast cancer cases and in unaffected women with a family history of cancer, but was also apparent in the unrelated control group, although the number of older controls was small. Polyak et al (1997) observed a reduced apoptotic response of lymphocytes to 5 Gy radiation in mice as they aged, and suggested that similar data on humans would be of interest. Suh et al (2002) found a reduced apoptotic response in rat liver cells exposed to methyl methane-sulphonate.…”

Section: Discussionmentioning

confidence: 78%

“…Polyak et al (1997) and Suh et al (2002), based on rodent data, that such a reduction may play an important role in age-associated disease processes. In relation to cancer specifically, this hypothesis is further supported by the reduced apoptotic response seen in breast cancer patients vs normal controls.…”

Section: Discussionmentioning

confidence: 99%

“…For example, Polyak et al (1997) observed a reduced apoptotic response of lymphocytes to 5 Gy radiation in mice with increasing age. Suh et al (2002) found a reduced apoptotic response in rat liver cells exposed to methyl methane-sulphonate.…”

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confidence: 99%

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Apoptosis, ageing and cancer susceptibility

et al. 2003

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We have previously shown that peripheral blood lymphocytes (PBL) from individuals carrying a germline TP53 mutation show a dramatically reduced apoptotic response to radiation. As part of a study of this phenomenon, we also investigated apoptotic response in a series of breast cancer patients lacking TP53 mutations and in a control group of individuals without cancer. There was a significant reduction in mean apoptotic response with increasing age in all groups. These findings are consistent with a number of studies in rodents, which have demonstrated a reduction in DNA damage-induced apoptosis with increasing age. In addition, after adjusting for age, breast cancer patients showed significantly reduced apoptotic responses compared with normal controls (P ¼ 0.002). The odds ratio for breast cancer in women with an apoptotic response of o35%, compared with women with a response of 449%, was 6.42 (95% CI 1.68 -24.6). The data further support the hypothesis that a reduction in apoptotic response to DNA damage with increasing age may play a significant role in the age-related increase in cancer.

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Section: Discussionmentioning

confidence: 78%

Section: Discussionmentioning

confidence: 99%

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Apoptosis, ageing and cancer susceptibility

et al. 2003

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“…Waf1 can occur as early as dysplastic aberrant crypt foci, the earliest detectable histological abnormalities and putative precursors of colon cancer (Polyak et al, 1996). We have demonstrated that PKC-d upregulates p21…”

Section: Kip2mentioning

confidence: 85%

Protein kinase C delta inhibits Caco-2 cell proliferation by selective changes in cell cycle and cell death regulators

et al. 2006

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PKC-d is a serine/threonine kinase that mediates diverse signal transduction pathways. We previously demonstrated that overexpression of PKC-d slowed the G1 progression of Caco-2 colon cancer cells, accelerated apoptosis, and induced cellular differentiation. In this study, we further characterized the PKC-d dependent signaling pathways involved in these tumor suppressor actions in Caco-2 cells overexpressing PKC-d using a Zn 2 þ inducible expression vector. Consistent with a G1 arrest, increased expression of PKC-d caused rapid and significant downregulation of cyclin D1 and cyclin E proteins (50% decreases, Po0.05), while mRNA levels remained unchanged. The PKC agonist, phorbol 12-myristate 13-acetate (TPA, 100 nM, 4 h), induced two-fold higher protein and mRNA levels of p21 Waf1, a cyclin-dependent kinase (cdk) inhibitor in PKC-d transfectants compared with empty vector (EV) transfected cells, whereas the PKC-d specific inhibitor rottlerin (3 lM) or knockdown of this isoenzyme with specific siRNA oligonucleotides blocked p21Waf1 expression. Concomitantly, compared to EV control cells, PKC-d upregulation decreased cyclin D1 and cyclin E proteins co-immunoprecipitating with cdk6 and cdk2, respectively. In addition, overexpression of PKC-d increased binding of cdk inhibitor p27Kip1 to cdk4. These alterations in cyclin-cdks and their inhibitors are predicted to decrease G1 cyclin kinase activity. As an independent confirmation of the direct role PKC-d plays in cell growth and cell cycle regulation, we knocked down PKC-d using specific siRNA oligonucleotides. PKC-d specific siRNA oligonucleotides, but not irrelevant control oligonucleotides, inhibited PKCd protein by more than 80% in Caco-2 cells. Moreover, PKC-d knockdown enhanced cell proliferation (B1.4-2-fold, Po0.05) and concomitantly increased cyclin D1 and cyclin E expression (B1.7-fold, Po0.05). This was a specific effect, as nontargeted PKC-f was not changed by PKC-d siRNA oligonucleotides. Consistent with accelerated apoptosis in PKC-d transfectants, compared to EV cells, PKC-d upregulation increased proapoptotic regulator Bax two-fold at mRNA and protein levels, while antiapoptotic Bcl-2 protein was decreased by 50% at a post-transcriptional level. PKC-d specific siRNA oligonucleotides inhibited Bax protein expression by more than 50%, indicating that PKC-d regulates apoptosis through Bax. Taken together, these results elucidate two critical mechanisms regulated by PKC-d that inhibit cell cycle progression and enhance apoptosis in colon cancer cells. We postulate these antiproliferative pathways mediate an important tumor suppressor function for PKC-d in colonic carcinogenesis.

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“…1B). By using radioactive thymidine and other markers of proliferation, it has been shown that the dysplastic cells at the orifices of the crypts have patterns expected of neoplastic cells whereas the cells at the base have normal proliferative patterns (4,5,8).…”

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confidence: 99%

Top-down morphogenesis of colorectal tumors

Shih

Wang

Traverso

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

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One of the fundamental tenets of oncology is that tumors arise from stem cells. In the colon, stem cells are thought to reside at the base of crypts. In the early stages of tumorigenesis, however, dysplastic cells are routinely found at the luminal surface of the crypts whereas the cells at the bases of these same crypts appear morphologically normal. To understand this discrepancy, we evaluated the molecular characteristics of cells isolated from the bases and orifices of the same crypts in small colorectal adenomas. We found that the dysplastic cells at the tops of the crypts often exhibited genetic alterations of adenomatous polyposis coli (APC) and neoplasia-associated patterns of gene expression. In contrast, cells located at the base of these same crypts did not contain such alterations and were not clonally related to the contiguous transformed cells above them. These results imply that development of adenomatous polyps proceeds through a top-down mechanism. Genetically altered cells in the superficial portions of the mucosae spread laterally and downward to form new crypts that first connect to preexisting normal crypts and eventually replace them.

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Less death in the dying

Cited by 21 publications

References 14 publications

Apoptosis, ageing and cancer susceptibility

Apoptosis, ageing and cancer susceptibility

Protein kinase C delta inhibits Caco-2 cell proliferation by selective changes in cell cycle and cell death regulators

Top-down morphogenesis of colorectal tumors

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