Cell cycle and apoptosis regulatory protein-1: a novel regulator of apoptosis in the colonic mucosa during aging

Du, Jianhua; Yu, Yingjie; Hu, Xu; Levi, Edi; Patel, Bhaumik B.; Rishi, Arun K.

doi:10.1152/ajpgi.00324.2007

Cited by 14 publications

(8 citation statements)

References 29 publications

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“…Earlier, as has been observed in the current investigation, the age-related increase in the expression of several markers of CSLC in the colonic mucosa is associated with a concomitant increase in EGFR expression, and these increases are exacerbated by DMH (16,34). Aging has also been shown to be associated activation of EGFR and its downstream signaling events (20,21). Our current data further demonstrate that administration of cetuximab, monoclonal antibodies to EGFR that inhibit EGFR activation, not only inhibits the expression of CSLC markers CD166 and ALDH-1 but also miR-21 expression in the colonic mucosa in both young and aged animals, but the magnitude of inhibition of these parameters is much greater in aged than that noted in young animals.…”

Section: Discussionsupporting

confidence: 79%

“…Our current data further demonstrate that administration of cetuximab, monoclonal antibodies to EGFR that inhibit EGFR activation, not only inhibits the expression of CSLC markers CD166 and ALDH-1 but also miR-21 expression in the colonic mucosa in both young and aged animals, but the magnitude of inhibition of these parameters is much greater in aged than that noted in young animals. Whether other members of the EGFR, specifically HER-2 and HER-3, which are also activated in the aging colon (21) and are known to play critical roles in the development and progression of many epithelial malignancies, including the colorectal cancer, play a role in the development of the CSLC phenotype remain to be determined.…”

Section: Discussionmentioning

confidence: 99%

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EGFR regulation of colon cancer stem-like cells during aging and in response to the colonic carcinogen dimethylhydrazine

Nautiyal

et al. 2012

American Journal of Physiology-Gastrointestinal and Liver Physi

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One of the most consistent pathological conditions in the gastrointestinal tract with advancing age is malignancy, particularly gastrointestinal cancers, the incidence of which increases sharply with aging. Although the reasons for the age-related rise in colorectal cancer are not fully understood, we hypothesize that aging increases susceptibility of the colon to carcinogen(s)/toxicant(s), leading to an increase in cancer stem-like cells (CSLCs) that express cancer stem cell markers, in the colonic mucosa. The current study demonstrates that aging is associated with increased expression of several colon CSLC markers [CD44, CD166, and aldehyde dehydrogenase 1 (ALDH-1)] and a higher proportion of cells expressing these markers. Aging is also accompanied by increased expression of miR-21 in colon. These increases are further increased in response to the colonic carcinogen dimethylhydrazine (DMH). Aging is also associated with increased tyrosine-phosphorylated epidermal growth factor receptor (EGFR). Inhibition of EGFR using the EGFR inhibitor cetuximab abrogated the age-related increase in CD166 and ALDH-1 as well as miRNA (miR)-21. Our results provide new evidence that aging and DMH are associated with increases in CSLC biomarkers and miR21, each of which have been linked to colorectal cancer. EGFR inhibition attenuates these changes, indicating a role for EGFR in age- and mutagen-associated changes in CSLCs.

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Section: Discussionsupporting

confidence: 79%

Section: Discussionmentioning

confidence: 99%

EGFR regulation of colon cancer stem-like cells during aging and in response to the colonic carcinogen dimethylhydrazine

Nautiyal

et al. 2012

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…The two proteins whose function in humans is to inhibit apoptosis, CAS and IAP, were significantly down-regulated by about 2-fold, yet apoptotic processes were not inhibited, at least after 2 d of feeding. The fact that CARP, a protein generally associated with an increase in apoptosis [63], did not respond to the diet suggests that there was no clear apoptosis induction in adult females in our experimental conditions. Buttino et al [64] using aldehyde-encapsulating liposomes observed apoptotic regions in copepod female gonads only after 9 d of feeding.…”

Section: Discussionmentioning

confidence: 80%

Molecular Evidence of the Toxic Effects of Diatom Diets on Gene Expression Patterns in Copepods

et al. 2011

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BackgroundDiatoms are dominant photosynthetic organisms in the world's oceans and are considered essential in the transfer of energy through marine food chains. However, these unicellular plants at times produce secondary metabolites such as polyunsaturated aldehydes and other products deriving from the oxidation of fatty acids that are collectively termed oxylipins. These cytotoxic compounds are responsible for growth inhibition and teratogenic activity, potentially sabotaging future generations of grazers by inducing poor recruitment in marine organisms such as crustacean copepods.Principal FindingsHere we show that two days of feeding on a strong oxylipin-producing diatom (Skeletonema marinoi) is sufficient to inhibit a series of genes involved in aldehyde detoxification, apoptosis, cytoskeleton structure and stress response in the copepod Calanus helgolandicus. Of the 18 transcripts analyzed by RT-qPCR at least 50% were strongly down-regulated (aldehyde dehydrogenase 9, 8 and 6, cellular apoptosis susceptibility and inhibitor of apoptosis IAP proteins, heat shock protein 40, alpha- and beta-tubulins) compared to animals fed on a weak oxylipin-producing diet (Chaetoceros socialis) which showed no changes in gene expression profiles.ConclusionsOur results provide molecular evidence of the toxic effects of strong oxylipin-producing diatoms on grazers, showing that primary defense systems that should be activated to protect copepods against toxic algae can be inhibited. On the other hand other classical detoxification genes (glutathione S-transferase, superoxide dismutase, catalase, cytochrome P450) were not affected possibly due to short exposure times. Given the importance of diatom blooms in nutrient-rich aquatic environments these results offer a plausible explanation for the inefficient use of a potentially valuable food resource, the spring diatom bloom, by some copepod species.

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“…In fact, the occurrence of both nonmalignant and malignant colorectal neoplasm increases with advancing age (4). Although the reasons for this increase is not fully understood, results from animal experimental models show that aging is associated with increased proliferation and attenuated apoptosis in both gastric and colonic mucosa, leading to increased susceptibility to cancer (5). This has in part been attributed to increased expression and activation of epidermal growth factor receptor (EGFR) and its family members in the gastrointestinal (GI) mucosa (4).…”

Section: Introductionmentioning

confidence: 99%

Age-related increase in colorectal cancer stem cells in macroscopically normal mucosa of patients with adenomas: A risk factor for colon cancer

Patel

et al. 2009

Biochemical and Biophysical Research Communications

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It is becoming increasingly evident that cancer stem cells play a vital role in development and progression of cancers and relapse following chemotherapy. The present study examines the presence of cancer stem-like cells (CSC) in adenomatous polyps and in normal appearing colonic mucosa in humans with aging. The number of polyps was found to increase linearly with advancing age (r 2 =0.92, p<0.02). Immunohistochemical analysis revealed co-localization of CSC markers CD44 and CD166 in colonic polyps. Real-time RT-PCR analysis of normal appearing mucosa from subjects with adenomatous polyps showed an age-related rise in CSC as evidenced by the increased expression of CD44, CD166 and ESA. A similar phenomenon was also observed for EGFR. In addition, the expression each CSC marker was found to be about 2-fold higher in subjects with 3-4 polyps than those with 1-2 polyps. In conclusion, our results show that colon cancer stem-like cells are present in the premaliganant adenomatous polyps as well in normal appearing colonic muocsa. Moreover, our observation of the age-related rise in CSC in macroscopically normal colonic mucosa suggests a predisposition of the organ to developing colorectal cancer.

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Cell cycle and apoptosis regulatory protein-1: a novel regulator of apoptosis in the colonic mucosa during aging

Abstract: Cell cycle and apoptosis regulatory protein-1: a novel regulator of apoptosis in the colonic mucosa during aging.

Cited by 14 publications

References 29 publications

EGFR regulation of colon cancer stem-like cells during aging and in response to the colonic carcinogen dimethylhydrazine

EGFR regulation of colon cancer stem-like cells during aging and in response to the colonic carcinogen dimethylhydrazine

Molecular Evidence of the Toxic Effects of Diatom Diets on Gene Expression Patterns in Copepods

Age-related increase in colorectal cancer stem cells in macroscopically normal mucosa of patients with adenomas: A risk factor for colon cancer

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