Biomedical subjects

S Fan

Publications and source records attributed to S Fan.

At least 73 records · Page 4Linked to original sources

PubMed1999

Assessment of genetic changes in hepatocellular carcinoma by comparative genomic hybridization analysis: relationship to disease stage, tumor size, and cirrhosis.

Hepatocellular carcinoma (HCC) is a common and highly malignant tumor that is prevalent in Southeast Asia. Although the etiological factors associated are now well recognized, the interactions between individual factors and the molecular mechanisms by which they lead to cancer remain unclear. Cytogenetic analysis on HCC has been limited because of poor hepatocyte growth in vitro. The recently developed technique of comparative genomic hybridization (CGH), however, permits screening of the entire genome without the need of cell culture. CGH was applied to the study of genomic aberrations in 67 surgically resected samples of HCC, 3 of adenomatous hyperplasia (AH), and 12 of nontumorous cirrhotic liver surrounding the tumors. All samples were from patients of a racially and etiologically homogeneous population in Southern China, where chronic hepatitis B virus infection is the main etiological factor. CGH analysis of the HCC samples revealed frequent copy number gain of 1q (48/67 cases, 72%), 8q (32/67 cases, 48%), 17q (20/67 cases, 30%), and 20q (25/67 cases, 37%) and common losses on 4q (29/67 cases, 43%), 8p (25/67 cases, 37%), 13q (25/67 cases, 37%), and 16q (20/67 cases, 30%). Our finding of a high incidence of 1q gain strongly suggested this aberration was associated with the development of HCC. Genomic abnormalities were detected in 1 of the 3 AH specimens but absent in all 12 cirrhotic tissues surrounding the tumor. Clinical staging classified 3/67 HCC cases as T1, 53 cases as T2, and 11 cases as T3. No significant difference in the pattern of genomic imbalances was detected between stages T2 and T3. A significant copy number loss of 4q11-q23 was, however, identified in those tumors larger than 3 cm in diameter. Of particular interest was the identification of 8q copy number gain in all 12 cases of HCC that arose in a noncirrhotic liver, compared with only 20/55 cases in HCC arising in a cirrhotic liver. We suggest that 8q over-representation is likely associated with a growth advantage and proliferative stimulation that have encouraged malignant changes in the noncirrhotic human liver.

Adult↗

PubMed1999

Long-term depot-medroxyprogesterone acetate and bone mineral density.

The association between long-term use of depot-medroxyprogesterone acetate (DMPA) and bone mineral density (BMD) has been controversial, as seen in three case-control studies in New Zealand, Thailand, and the United Kingdom. In the present case-controlled study of BMD, a group of 67 Chinese women who had used DMPA from 5-15 years was compared with 218 women of the same age range who had not used any steroidal hormones. DMPA users were found to have a significantly lower BMD at lumbar vertebra (L2-4) (0.93 g/cm2), neck of femur (0.69 g/cm2), trochanter (0.59 g/cm2), and Ward's triangle (0.58 g/cm2), as compared with the control group, whose corresponding BMD values were 1.03 g/cm2, 0.83 g/cm2, 0.71 g/cm2, and 0.78 g/cm2, respectively (p < 0.001). The average percentage of bone loss per year was estimated to be 1.1% in L2-4, 2.3% in neck of femur, 2.4% in trochanter, and 3.5% in Ward's triangle. The percentage of bone loss in L2-4 was found to be more pronounced with age. This study provided information that the use of DMPA in a Chinese group for > 5 years in associated with bone loss, and a prospective study is needed to confirm these data, which are different from two case-control studies.

Absorptiometry, Photon↗

PubMed1999

Superiority of the combination of blood and agitated saline for routine contrast enhancement.

The purpose of this study was to evaluate the modification of the saline echo contrast method by mixing blood with agitated saline before intravenous injection. In 20 patients, contrast echocardiography was performed with a conventional technique from the apical 4-chamber view. We used 2 techniques: (1) the combination of blood (1 mL) withdrawn from the patients and air-agitated saline agitated, (2) air-agitated. In all patients, the blood combination technique was judged to make a greater contrast, with the agreement of all 3 reviewers. Peak echo intensity of the right ventricular cavity by the blood combination technique was significantly higher than that by agitated saline alone. In conclusion, the use of the combination of blood and agitated saline is superior to agitated saline alone for the opacification of the right atrium and ventricle in routine echocardiography.

Aged↗

PubMed1999

Attention-sensitive visual event-related potentials elicited by kinetic forms.

Previous event-related potential (ERP) studies have shown that selectively attending to a relevant stimulus feature was associated with selection negativity (SN) components. The present study aimed at investigating the ERP indices of attentional selection based on forms defined by motion (kinetic forms). ERPs were recorded from subjects who attended selectively to sequentially presented kinetic forms of bars in one visual field and detected occasional tilted bar targets. Two kinds of kinetic forms were used as the visual stimuli in separate experiments. The main findings were that spatial attention enhanced the amplitude of early ERP components 1 and N1 as well as the late component N2. Topographic maps of voltage and low resolution electromagnetic tomography (LORETA) of the dN2 wave (difference waveform between N2 under attended condition and N2 under unattended condition) suggested an origin in the right occipitotemporal cortex. According to its timing and morphology, the dN2 wave was considered to be an endogenous ERP (like the SN) and was interpreted as reflecting attentional facilitation of the processing of forms defined by motion primarily involving the right occipitotemporal areas.

Adult↗

PubMed1999

Modulation of brain activities by hierarchical processing: a high-density ERP study.

The present study investigated how attention to global or local levels of hierarchical patterns modulates brain activities by recording high-density event-related brain potentials (ERPs) evoked by hierarchical stimuli. 120-channel recordings of ERPs were obtained from subjects while they detected targets at global or local levels of hierarchical stimuli displayed in the left or the right visual field. We found that attention to local stimulus features enhanced posterior P1 and N2 components, with the N2 enhancement showing a left hemisphere predominance regardless of stimulus positions. Difference was also seen in the distribution of the frontal P2. Reaction times were slowed when global and local levels of stimuli were incompatible, and an interference effect was observed on anterior N2 amplitudes and latencies. Three-dimensional current distributions showed common sources over the posterior cortex between 80-230 ms and a contralateral frontal source between 300-400 ms for global and local conditions. However, an additional ipsilateral frontal focus between 230-350 ms was found specially for local processing. The results corroborate the findings of previous ERP studies, and suggest that the frontal lobe is particularly important for the selective processing of local parts of a global structure.

Adult↗

PubMed1999

Ultraviolet radiation down-regulates expression of the cell-cycle inhibitor p21WAF1/CIP1 in human cancer cells independently of p53.

PURPOSE: To investigate the regulation of G1 cyclin-dependent kinase inhibitor p21WAF1/CIP1 by ultraviolet (UV) radiation in human carcinoma cells. MATERIALS AND METHODS: Human cancer cell lines were irradiated with UV-C (254 nm) radiation, and their responses were characterized by Western blotting, Northern blotting, semi-quantitative RT-PCR analysis, trypan blue staining and flow cytometric cell cycle analysis. RESULTS: At 24 h after UV irradiation, p21 expression was down-regulated in various cancer cell types (breast, prostrate, cervix, colon, glioma, squamous cancers), independently of their p53 genetic and functional status. UV-mediated down-regulation of p21 was dose- and time-dependent, was observed at the protein and mRNA levels, and did not correlate with cytotoxicity. Reduction of p21 protein levels required about 4 and 1 h, respectively, in MCF-7 and MDA-MB-231 breast cancer cells; some of the UV-induced decreases in p21 levels in these cell lines was due to enhanced proteasomal degradation. Despite decreased p21 levels, UV-irradiated breast cancer cells with wild-type p53 (MCF-7) retained the capacity for G1 cell-cycle arrest, whereas UV-treated cells with mutant p53 (MDA-MB-231) accumulated in S phase, suggesting a p53-dependent G1 checkpoint in MCF-7. UV treatment caused other alterations in cell-cycle regulatory, DNA repair and tumour suppressor genes, as described in this report. CONCLUSIONS: In contrast to X-rays, UV causes down-regulation of the cell-cycle inhibitor p21 in tumour cells. It is postulated that this may be an adaptation to promote the growth and survival of transformed cells.

BRCA2 Protein↗

PubMed1999

Mainstream and sidestream cigarette smoke condensates suppress macrophage responsiveness to interferon gamma.

Sidestream smoke evolves from the smoldering end of a cigarette while the smoker is not puffing, and contributes substantially to environmental tobacco smoke (ETS). In contrast, main stream smoke emerges from the butt end of the cigarette and is mainly inhaled by the smoker. This study was performed to compare the effects of short-term exposure to cigarette smoke condensates prepared from sidestream (CSC-SS) and mainstream cigarette smoke (CSC-MS) on macrophage basal metabolism and responsiveness to two different stimuli, bacterial lipopolysaccharide (LPS) and interferon gamma (IFNgamma). Despite their generation at different temperatures and their different chemical composition, CSC - SS and CSC - MS had similar effects on macrophages. Both enhanced macrophage basal metabolism and responsiveness to LPS. Macrophage responsiveness to IFNgamma, assessed by their expression of four functional capacities, was suppressed by both CSC-SS and CSC-MS. The four assessed IFNgamma-inducible functional capacities were: enhanced phagocytosis of immuoglobulin-opsonized sheep red blood cells, TPA-induced peroxide production, class II major histocompatibility complex expression, and nitric oxide synthesis with LPS co-stimulation. The effects of CSC - SS and CSC - MS were similar qualitatively; they differ quantitatively in some cases, with CSC-MS generally effective at lower concentrations (expressed as cigarette-equivalents) than CSC-SS. Considering dilution of sidestream smoke in room air and loss during passage through the respiratory system, we expect to deliver the maximal dose to lung macrophages in situ only in rooms dense with smokers. However, only a fraction of the maximal dose can partially suppress induction of some functions, such as nitric oxide production and MHC expression. Macrophages play critical roles in tissue modeling during development. Of particular concern are neonates, whose organs are still undergoing growth and development, and are therefore susceptible to impaired development. If involuntary exposure to ETS hinders induction of macrophage functional capacities by cytokines, then development of the lungs and perhaps other organs would be impaired. In general, since macrophages are potent effectors and regulators of immunity, impairment of their responsiveness to cytokine must disrupt the proper functioning of the immune system.

Animals↗

PubMed1999

Relationship between ventral stream for object vision and dorsal stream for spatial vision: an fMRI + ERP study.

Recent imaging studies indicated the existence of two visual pathways in humans: a ventral stream for object and form vision and a dorsal stream for spatial and motion vision. The present study was motivated by a stimulating question: Supposing shape and motion are processed separately in the two pathways, how do the respective cortical areas respond to the stimuli of "forms defined by motion"? fMRI and ERP recordings were combined in order to measure the spatiotemporal activation pattern in the two pathways responding to forms defined by motion, which were produced solely by coherent movement of random dots against a background of dynamic or static random dots. The fMRI data indicated that the stimuli of forms defined by motion indeed activated both dorsal MT/V5 and ventral GTi/GF. Furthermore, the RV curves resulting from fMRI-seeded dipole modeling indicated that each pair of dipoles located at MT/V5 or GTi/GF reached the same best-fit point; a single pair of free dipoles located near the fMRI foci of MT/V5 and GTi/GF could be identified at the corresponding best-fit point; and the source waveforms resulting from fixed dipole modeling also showed simultaneous activation of MT/V5 and GTi/GF dipoles in the time interval around the best-fit point. The present results, therefore, suggest that MT/V5 and GTi/GF appear to be activated in parallel and simultaneously responding to forms defined by motion. Such findings raise interesting issues about the hierarchical organization and the functional specialization in the two pathways.

Adult↗

PubMed1999

The molecular and cellular basis of radiosensitivity: implications for understanding how normal tissues and tumors respond to therapeutic radiation.

We have provided an overview of recent studies that have greatly expanded our knowledge of the molecular and cellular mechanisms that determine the sensitivity or resistance to ionizing radiation. Much of this knowledge was obtained by studying tumor and nontumor cell types that under- or overexpress proteins involved in the regulation of the DNA damage response, cell cycle progression, growth factor signal transduction, and apoptosis. These findings may ultimately be useful in devising new strategies to improve the therapeutic ratio in cancer treatment. Despite the rapid advances in knowledge of cellular functions that affect radiosensitivity, we still cannot account for most of the clinically observed heterogeneity of normal tissue and tumor responses to radiotherapy; nor can we accurately predict which individual tumors will be locally controlled and which patients will develop more severe normal tissue damage after radiotherapy. However, several candidate genes for which deletion or loss of function mutations may be associated with altered cellular radiosensitivity (e.g., ATM, p53, BRCA2) have been identified. Some of the differences in normal tissue sensitivity to radiation may occur because of mutations with milder effects, heterozygosity, or polymorphisms of these genes. Finally, molecular mechanisms linking genetic instability, radiosensitivity, and predisposition to cancer are being examined.

Acute Disease↗

PubMed1999

Interrelation between nitric oxide and endothelin-1 in an experimental acute hypoxia in rats and its intervention.

OBJECTIVES: To study the interrelation between nitric oxide (NO) and endothelin-1 (ET1) in experimental acute hypoxic rats, and to evaluate the mechanism of acute hypoxic pulmonary hypertension affected by NO and ET1 and its intervention. METHODS: Nicotinamide adenine dinucleotide phosphate (NADPH) diaphorase histochemical staining method, Griess biochemical assay and radioimmune assay were applied to investigate the changes of nitric oxide syntheses (NOS), NO and ET1 in normal, hypoxic, and L-Arginine (L-Arg) and dexamethasone treated hypoxic rats. RESULTS: In normal rats, the NOS stain was localized in pulmonary vascular endothelium, and in the hypoxic rats, the activity of NOS was significantly lower. The level of plasma NO was significantly lower during acute hypoxia, but L-Arg as well as dexamethasone could prevent the drop of plasma NO. The level of plasma ET1 rose up significantly in the acute hypoxic rats, but after L-Arg therapy, it was significantly reduced, however, dexamethasone could not affect plasma ET1. The level of plasma cyclic guanosine monophosphate (cGMP) was significantly lower in the acute hypoxic rats, and L-Arg could prevent the drop of plasma cGMP, but dexamethasone could not prevent the drop of plasma cGMP. CONCLUSIONS: NO and ET1 may modulate hypoxic pulmonary hypertension and acute hypoxia can result in acute hypoxic pulmonary hypertension. L-Arg can reverse the acute hypoxic pulmonary hypertension. Further study is needed if dexamethasone is beneficial in acute hypoxic diseases. NO may play an important role in physiology of the lung and acute hypoxic diseases.

Animals↗

PubMed1999

Repair of stricture of cervical esophagus with platysma myocutaneous flaps.

OBJECTIVE: To observe the effect of repairing stricture of the cervical esophagus with platysma myocutaneous flaps. METHODS: Fifteen patients with stricture of the cervical esophagus were treated by repair with platysma myocutaneous flaps. The causes of stricture included anastomotic stenosis of the cervical esophagus after colon graft transplantation due to esophageal caustic injury (12 patients), anastomotic stenosis after stomach transposition due to resection of the upper esophageal cancer (2), and stricture caused by limited erosive injury of the cervical esophagus (1). The lengths of stricture were about 3.5-4.5 cm. The stricture was incised longitudinally. The platysma myocutaneous flaps about 4 cm-5 cm x 6 cm-7 cm were resected and were transposed to repair the stricture. RESULTS: All flaps survived and no death or serious complications occurred after operation. All patients gained normal functions in swallowing food. CONCLUSION: Repairing stricture of the cervical esophagus with platysma myocutaneous flaps is simple, safe and effective.

Adolescent↗

PubMed1999

Messenger RNA expressions of vasopressin system and aquaporin-2 in adriamycin-induced nephrotic rats and effects of astragalus membranaceus.

OBJECTIVE: To investigate the expressions of hypothalamic arginine vasopressin (AVP) mRNA, renal AVP V2 receptor mRNA, and AVP-dependent aquaporin-2 (AQP2) mRNA in rats with adriamycin-induced nephrotic syndrome. Effects of Chinese herb Astragalus membranaceus (AM) were also tested. METHODS: Sprague-Dawley rats with four weeks of adriamycin-induced nephrotic syndrome (NS) were used in this study. Another group NS + AM was set to testify the effects of AM given 0.5 g/kg daily on NS. Hypothalamic AVP mRNA expression was examined by dot blot method. Reverse transcription polymerase chain reaction was applied for detection of renal cortical and medullary V2 receptor and AQP2 mRNA. The results were normalized by mRNA of glyceraldehyde-3-phosphate dehydrogenase from the same sample. RESULTS: All rats receiving adriamycin presented typical nephrosis. No obvious difference in plasma osmolality was detected among NS, NS + AM, and normal control (NC) rats. Hypothalamic AVP mRNA expression was higher in NS rats than NC (53.59 +/- 5.49 vs 25.72 +/- 1.96, P < 0.01). AM completely reversed this up-regulated expression (21.88 +/- 1.25). In both cortex and medulla of the kidney, nephrotic rat had increased AVP V2 expressions by 169% and 55%, respectively, compared with normal control rat. The increment of expression of AQP2 mRNA was consistent with that of V2 receptor in NS rat. AM could partially however significantly correct these up-regulations of V2 and AQP2 mRNA expressions (P < 0.01). CONCLUSION: The up-regulated mRNA expressions of hypothalamic AVP, renal V2 receptor and AQP2 might play a role in edema formation in adriamycin-induced nephrotic rats. AM exerts its therapeutical effects on nephrosis partially through this mechanism.

Animals↗

PubMed1999

Guidelines for the administration of hormone replacement therapy. The Hong Kong College of Obstetricians and Gynaecologists.

OBJECTIVES: To establish guidelines on the administration of hormone replacement therapy in Hong Kong for a primary audience of Fellows and Members of the Hong Kong College of Obstetricians and Gynaecologists and a secondary audience of all interested medical and paramedical personnel in Hong Kong. PARTICIPANTS: The Quality Assurance Committee established a consensus panel of four College Fellows who had expertise of treating menopausal women by giving hormone replacement therapy. All the panelists were qualified obstetricians and gynaecologists. EVIDENCE: The panelists drew their conclusions from the available scientific literature on hormone replacement therapy from Hong Kong and overseas. CONSENSUS PROCESS: The consensus reached within the panel was presented to the Quality Assurance Committee on 23 June 1998, and subsequently revised and presented three times. The final version was approved by the Quality Assurance Committee on 2 March 1999 and the Council of the Hong Kong College of Obstetrics and Gynaecology on 11 March 1999. CONCLUSIONS: The administration of hormone replacement therapy is effective in reducing the severity and frequency of menopausal hot flushes and sweating. Therapy protects against osteoporosis and reduces the risk of cardiovascular disease. There is some evidence to suggest that treatment also protects against Alzheimer's disease and carcinoma of the colon. The most serious problem attributed to using hormone replacement therapy is the possible increase in the risk of breast cancer development; the exact risk is unknown. Side effects include unwanted bleeding and breast tenderness and sensitivity. The risks and benefits of using hormone replacement therapy should be explained to postmenopausal women so that they can make an informed decision about using this treatment.

Journal Article↗

PubMed1998

A dielectric omnidirectional reflector

A design criterion that permits truly omnidirectional reflectivity for all polarizations of incident light over a wide selectable range of frequencies was used in fabricating an all-dielectric omnidirectional reflector consisting of multilayer films. The reflector was simply constructed as a stack of nine alternating micrometer-thick layers of polystyrene and tellurium and demonstrates omnidirectional reflection over the wavelength range from 10 to 15 micrometers. Because the omnidirectionality criterion is general, it can be used to design omnidirectional reflectors in many frequency ranges of interest. Potential uses depend on the geometry of the system. For example, coating of an enclosure will result in an optical cavity. A hollow tube will produce a low-loss, broadband waveguide, whereas a planar film could be used as an efficient radiative heat barrier or collector in thermoelectric devices.

Journal Article↗

PubMed1998

A large terrestrial carbon sink in north america implied by atmospheric and oceanic carbon dioxide data and models

Atmospheric carbon dioxide increased at a rate of 2.8 petagrams of carbon per year (Pg C year-1) during 1988 to 1992 (1 Pg = 10(15) grams). Given estimates of fossil carbon dioxide emissions, and net oceanic uptake, this implies a global terrestrial uptake of 1.0 to 2. 2 Pg C year-1. The spatial distribution of the terrestrial carbon dioxide uptake is estimated by means of the observed spatial patterns of the greatly increased atmospheric carbon dioxide data set available from 1988 onward, together with two atmospheric transport models, two estimates of the sea-air flux, and an estimate of the spatial distribution of fossil carbon dioxide emissions. North America is the best constrained continent, with a mean uptake of 1.7 +/- 0.5 Pg C year-1, mostly south of 51 degrees north. Eurasia-North Africa is relatively weakly constrained, with a mean uptake of 0.1 +/- 0.6 Pg C year-1. The rest of the world's land surface is poorly constrained, with a mean source of 0.2 +/- 0.9 Pg C year-1.

Journal Article↗

PubMed1998

Down-regulation of BRCA1 and BRCA2 in human ovarian cancer cells exposed to adriamycin and ultraviolet radiation.

Germ-line mutations of the BRCA1 and BRCA2 genes predispose women to develop cancers of the breast and ovary, but the biologic functions of these genes remains unclear. We have investigated the responses of the BRCA1 and BRCA2 gene products to cytotoxic agents in 3 human ovarian cancer cell lines: SK-OV-3 (which contains a p53 deletion mutation), CAOV-3 (which over-expresses a mutant p53) and PA-1 (which expresses wild-type p53). In screening studies, we determined the effects of 7 different agents on BRCA1 and BRCA2 expression. We found that Adriamycin (ADR) and ultraviolet (UV)radiation significantly down-regulated BRCA1 and BRCA2 mRNA expression in SK-OV-3 cells. On the other hand, camptothecin, nitrogen mustard, taxol, vincristine and etoposide had no effect on BRCA1 or BRCA2 mRNA levels at doses that yielded degrees of cytotoxicity similar to or greater than ADR. The down-regulation of BRCA1 and BRCA2 mRNAs was dose and time dependent; significant down-regulation was first observed at 8-16 hr after exposure to ADR. BRCA1 protein levels were also down-regulated following treatment of SK-OV-3 cells with ADR. Similar results were observed in CAOV-3 and PA-1 cells treated with ADR, and this finding could not be directly attributed to ADR-induced changes in the cell cycle distribution. The ADR doses required for significant decreases of BRCA1 and BRCA2 were about 10-15, 5-10 and 2 microM, respectively, for SK-OV-3, CAOV-3 and PA-1; the IC50 doses for loss of cell viability (determined by Trypan blue dye exclusion) were 23, 14 and 0.4 microM, respectively. Thus, at equitoxic doses of ADR, PA-1 cells were more resistant to down-regulation of BRCA1 and BRCA2 than SK-OV-3 or CAOV-3. Our findings suggest that 1) BRCA1 and BRCA2 expression in human ovarian cancer cell lines is selectively down-regulated by 2 DNA-damaging agents (ADR and UV radiation); 2) these responses are not due to non-specific cytotoxicity; and 3) the BRCA1 and BRCA2 responses may be dependent, in part, on the p53 functional status of the cells. We speculate that the down-regulation of BRCA1 and BRCA2 may be part of a cellular survival response activated by certain forms of DNA damage.

Antibiotics, Antineoplastic↗

PubMed1998

Distinct apoptotic responses imparted by c-myc and max.

The c-myc oncoprotein accelerates programmed cell death (apoptosis) after growth factor deprivation or pharmacological insult in many cell lines. We have shown that max, the obligate c-myc heterodimeric partner protein, also promotes apoptosis after serum withdrawal in NIH3T3 fibroblasts or cytokine deprivation in interleukin-3 (IL-3)-dependent 32D murine myeloid cells. We now show that c-myc- and max-overexpressing 32D cells differ in the nature of their apoptotic responses after IL-3 removal or treatment with chemotherapeutic compounds. In the presence of IL-3, c-myc overexpression enhances the sensitivity of 32D cells to Etoposide (Sigma, St Louis, MO), Adriamycin (Pharmacia, Columbus, OH), and Camptothecin (Sigma), whereas max overexpression increases sensitivity only to Camptothecin. Drug treatment of c-myc-overexpressing cells in the absence of IL-3 did not alter the spectrum of drug sensitivity other than to additively accelerate cell death. In contrast, enhanced sensitivity to Adriamycin, Etoposide, and Taxol (Bristol-Meyers Squibb, Princeton, NJ) was revealed in max-overexpressing cells concurrently deprived of IL-3. Differential rates of apoptosis were not strictly correlated with the ability of the drugs to promote G1 or G2/M arrest. Ectopic expression of Bcl-2 or Bcl-XL blocked drug-induced apoptosis in both cell lines. In contrast, whereas Bcl-2 blocked apoptosis in both cell lines in response to IL-3 withdrawal, Bcl-XL blocked apoptosis in max-overexpressing cells but not in c-myc-overexpressing cells. These results provide mechanistic underpinnings for the idea that c-myc and max modulate distinct apoptotic pathways.

Animals↗

PubMed1998

Scatter factor protects epithelial and carcinoma cells against apoptosis induced by DNA-damaging agents.

Scatter factor (SF) (hepatocyte growth factor) is a cytokine that may play a role in human breast cancer invasiveness and angiogenesis. We now report that SF can block the induction of apoptosis by various DNA damaging-agents, including cytotoxic agents used in breast cancer therapy. SF protected MDA-MB-453 human breast cancer cells, EMT6 mouse mammary tumor cells and MDCK renal epithelial cells against apoptosis induced by adriamycin (ADR), X-rays, ultraviolet radiation, and other agents. Protection was observed in assays of DNA fragmentation, cell viability (MTT), and clonogenic survival. Protection of MDA-MB-453 cells against ADR was dose- and time-dependent; maximal protection required pre-incubation with 75-100 ng/ml of SF for 48 h or more. Protection required functional SF receptor (c-Met), but was not dependent on p53. Western blotting analysis revealed that pre-treatment of MDA-MB-453 cells with SF inhibited the ADR-induced decreases in the levels of Bcl-XL, an anti-apoptotic protein related to Bcl-2; and the dose-response and time course characteristics for SF-mediated increases in the Bcl-XL protein levels of ADR-treated cells were consistent with the degrees of protection against apoptosis observed under the same conditions. Furthermore, Bcl-XL levels were not down-regulated by ADR in MDA-MB-231 breast cancer cells, consistent with the finding that SF failed to protect these cells against ADR, despite the fact that they contain functional c-Met receptor. In contrast to Bcl-XL, SF blocked ADR-induced increases in c-Myc and inhibited the expression of p21WAF1/CIP1 and of the BRCA1 protein in MDA-MB-453 cells. However, SF did not cause significant changes in the cell cycle distribution of ADR-treated cells. These findings suggest that SF-mediated protection of human breast cancer cells may involve inhibition of one or more pathways required for the activation of apoptosis and may particularly target the anti-apoptotic mitochondrial membrane pore-forming protein Bcl-XL as a component of the protective mechanism. By implication, the accumulation of SF within human breast cancers may contribute to the development of a radio- or chemoresistant phenotype.

Animals↗