Suppression of apoptosis by overexpression of Bcl-2 or Bcl-xL promotes survival and mutagenesis after oxidative damage

Cherbonnel, Corinne; Dosanjh, Manjit

doi:10.1016/s0300-9084(97)82011-1

Cited by 73 publications

(45 citation statements)

References 22 publications

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“…Overexpression of Bcl-2 or Bcl-xl inhibits apoptosis and promotes survival of cells (23). According to Zhu et al, the induction of Bax is essential for death receptor-mediated apoptosis in human colon cancer cells (24).…”

Section: Discussionmentioning

confidence: 99%

Carnosol induces apoptosis through generation of ROS and inactivation of STAT3 signaling in human colon cancer HCT116 cells

Park

Chae

Kim

et al. 2014

International Journal of Oncology

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Abstract. Carnosol, an active constituent of rosemary, has been reported to possess anti-inflammatory and anticancer activities. However, the molecular mechanisms underlying the anticancer effects of carnosol remain poorly understood. In the present study, we found that carnosol significantly reduced the viability of human colon cancer (HCT116) cells in a concentration-and time-dependent manner. Treatment of cells with carnosol induced apoptosis, which was associated with activation of caspase-9 and -3 and the cleavage of poly-(ADP-ribose) polymerase (PARP). Incubation with carnosol elevated the expression of Bax and inhibited the levels of Bcl-2 and Bcl-xl. Carnosol induced expression of p53 and inhibited that of murine-double minute-2 (Mdm2). Moreover, carnosol generated reactive oxygen species (ROS), and pretreatment with N-acetyl cysteine abrogated carnosol-induced cleavage of caspase-3 and PARP. The constitutive phosphorylation, the DNA binding and reporter gene activity of signal transducer and activator of transcription-3 (STAT3) was diminished by treatment with carnosol. To further elucidate the molecular mechanisms of STAT3 inactivation, we found that carnosol attenuated the phosphorylation of Janus-activated kinase-2 (Jak2) and Src kinase. Pharmacological inhibition of Jak2 and Src inhibited STAT3 phosphorylation. Furthermore, carnosol attenuated the expression of STAT3 target gene products, such as survivin, cyclin-D1, -D2, and -D3. Taken together, our study provides the first report that carnosol induced apoptosis in HCT116 cells via generation of ROS, induction of p53, activation of caspases and inhibition of STAT3 signaling pathway. IntroductionDespite a declining trend worldwide, colorectal cancer still remains as the third most common cancer among men and the second in women (1,2). More than one million new cases of colorectal cancer are diagnosed every year (3). A wide variety of natural compounds derived from edible plants have been shown to prevent colon carcinogenesis (4). Carnosol, a diterpene present in rosemary (Rosmarinus officinalis), has been reported to prevent the development of intestinal tumors in APC (adenomatous polyposis coli) min+/+ mice (5) and to induce apoptosis in human colon cancer (COLO 205) cells (6). However, the molecular mechanisms underlying the chemopreventive and/or chemotherapeutic effects of carnosol in colon cancer are yet to be fully elucidated. We, therefore, attempted to investigate the effects of carnosol on human colon cancer (HCT116) cells and to elucidate its underlying mechanisms.One of the hallmarks of cancer is the evasion of tumor cells from apoptosis (7). Numerous naturally occurring polyphenols inhibit proliferation and induce apoptosis in various cancer cells (8). Apoptosis is induced by two cellular mechanisms: intrinsic (mitochondria-dependent) and extrinsic (death receptor-mediated) signaling (9). The intrinsic pathway of apoptosis involves the depolarization of mitochondrial membrane, release of cytochrome c, sequential activation of caspase-9, ...

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Section: Discussionmentioning

confidence: 99%

Carnosol induces apoptosis through generation of ROS and inactivation of STAT3 signaling in human colon cancer HCT116 cells

Park

Chae

Kim

et al. 2014

International Journal of Oncology

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“…Suppression of apoptosis is reported to increase mutation frequency (30), and loss of apoptosis is associated with accumulation of oncogenes (31). By delaying cell death, the Bcl-2 protein may help to promote the accumulation of mutations, allowing cancer cells to acquire a more malignant phenotype.…”

Section: Figurementioning

confidence: 99%

Prognostic Significance of Glutathione S-Transferase-Pi in Invasive Breast Cancer

et al. 2003

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Glutathione S-transferase pi (GST-pi), a Phase II detoxification enzyme, has recently been implicated in protection against apoptosis. Expression of GST-pi and Bcl-2 protein, an established apoptosis marker, was analyzed by immunohistochemistry in 116 cases of infiltrative ductal breast carcinomas in Singapore women. The markers were correlated with apoptosis detected by the TUNEL method and clinico-pathological parameters. There were 67 (58%) GST-pi-positive breast tumors and 43 (37%) Bcl-2-positive tumors. In a large proportion of GSTpi-positive/Bcl-2-positive tumors, there was a distinct accumulation of the GST-pi enzyme within the nucleus of cancer cells when examined by double immunofluorescence labeling under confocal microscopy. GST-pi immunoreactivity was not significantly correlated with any of the traditional histologic factors known to influence prognosis, whereas Bcl-2 overexpression was associated with reduced size of primary tumor (P ‫؍‬ .021) and positive estrogen receptor status (P ‫؍‬ .001). Univariate analysis revealed that GST-pi-positive, Bcl-2-positive, and lower histological grade tumors had decreased levels of apoptosis (P ‫؍‬ .024, P ‫؍‬ .011, and P ‫؍‬ .029, respectively). However, multivariate analysis showed that histological grade and Bcl-2, but not GST-pi, immunoreactivity were correlated with apoptotic status. The Kaplan-Meier disease-free survival curves showed a significant difference between GST-pi-positive and GST-pi-negative breast cancer cases (P ‫؍‬ .002). Disease-free survival in patients with GST-pi-positive tumors was also worse than that in patients with GST-pi-negative tumors in the group who had adjuvant chemotherapy (P ‫؍‬ .04). In patients who were lymph node positive, GST-pi immunopositivity was found to influence disease-free survival. Recurrence of tumors was also significantly affected by GST-pi immunoreactivity (relative risk of 8.1). The findings indicate that GST-pipositive tumors are more aggressive and have a poorer prognosis than do corresponding GST-pinegative breast cancers.

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“…The calculations show that inactivation has a large effect on the expression of mutants for heavy ions. Experiments comparing the expression of mutation at the HPRT and TK loci in human lymphoid cells that are wild-type or mutant for p53 protein show increased levels of mutation in the mutant p53 cell lines [53]. Mutant p53 cell lines will have diminished apoptosis capacity after radiation exposure such that the survival response becomes more resistant.…”

Section: Amorphous Track Models Of Radiation Actionmentioning

confidence: 99%

Applications of amorphous track models in radiation biology

Cucinotta

Nikjoo

Goodhead

1999

Radiation and Environmental Biophysics

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The average or amorphous track model uses the response of a system to gamma-rays and the radial distribution of dose about an ion's path to describe survival and other cellular endpoints from proton, heavy ion, and neutron irradiation. This model has been used for over 30 years to successfully fit many radiobiology data sets. We review several extensions of this approach that address objections to the original model, and consider applications of interest in radiobiology and space radiation risk assessment. In the light of present views of important cellular targets, the role of target size as manifested through the relative contributions from ion-kill (intra-track) and gamma-kill (inter-track) remains a critical question in understanding the success of the amorphous track model. Several variations of the amorphous model are discussed, including ones that consider the radial distribution of event-sizes rather than average electron dose, damage clusters rather than multiple targets, and a role for repair or damage processing.

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Suppression of apoptosis by overexpression of Bcl-2 or Bcl-xL promotes survival and mutagenesis after oxidative damage

Cited by 73 publications

References 22 publications

Carnosol induces apoptosis through generation of ROS and inactivation of STAT3 signaling in human colon cancer HCT116 cells

Carnosol induces apoptosis through generation of ROS and inactivation of STAT3 signaling in human colon cancer HCT116 cells

Prognostic Significance of Glutathione S-Transferase-Pi in Invasive Breast Cancer

Applications of amorphous track models in radiation biology

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