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Department of Medicine I, University of Regensburg, 93042 Regensburg, Germany
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Abstract |
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Introduction |
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TOPAbstractIntroductionResultsDiscussionMaterials and MethodsReferences |
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IECs are generated by stem cells at the crypt base and migrate toward the intestinal lumen within only 3–5 days (1) . At the villus tip (in the small bowel) or luminal surface (in the large bowel), respectively, their short life cycle is terminated as these cells undergo apoptosis, loose anchorage, and shed into the lumen (2, 3, 4) . Induction of apoptosis by loss of cell anchorage, a form of apoptosis termed "anoikis" (5) , is likely to be one the mechanisms terminating the physiological life cycle of these cells because IECs seem to gradually loosen cell anchorage approaching the lumen: changes of integrin expression and cadherin binding, as well as the changing expression of basement membrane components, mediate an antiadhesive environment, culminating in detachment of the dying enterocyte at the villus tip/luminal surface (6, 7, 8, 9, 10, 11) . However, the molecular mechanisms of IEC apoptosis/shedding and the means of cell death execution poorly characterized. This process needs to be highly regulated and fast to maintain integrity of the intestinal epithelium.
Caspases, a newly defined group of cysteine proteases (12) , play a central role during apoptosis. They mediate the intracellular activation of other caspases and selectively cleave distinct intracellular substrates, leading to dismantling of a cell’s architecture, signaling apparatus, and repair mechanisms. Eventually, caspases induce the activation of endonucleases that complete cellular suicide by internucleosomal DNA fragmentation (13, 14, 15) . Caspases are divided into two groups, based on their assumed role in the apoptotic cascade (reviewed in Ref. 16 ). Whereas long-prodomain caspases (caspase-2, -8, -9, and -10) are regarded as "initiator caspases" functioning upstream in the cascade, short-prodomain caspases (caspase-3, -6, and -7) are regarded as downstream "executioner caspases." Similar to the complement system, caspases are believed to become activated in a hierarchical cascade, yet the exact mechanisms of activation and the sequence of events are still incompletely understood. Studies on the cascade of caspase activation during receptor-mediated apoptosis, radiation-induced apoptosis, or chemically induced apoptosis show that distinct cascades might be activated, depending on the form of apoptosis being executed (17, 18, 19, 20) . During certain forms of apoptosis and in certain cell types, the mitochondrial release of cytochrome c leading to the formation of the so-called apoptosome seems to play an important role as an initiating and augmenting factor of apoptotic signaling (21, 22, 23) .
Programmed cell death can be induced by several means, one of which is loss of cell anchorage in adherent cells. Meredith et al. (24) first described endothelial cells dying of apoptosis due to loss of anchorage in 1993, and Frisch and Francis (5) proposed the term anoikis for this form of apoptosis. Anoikis has been described for an array of adherent cells including mammary cells (25 , 26) , kidney cells (5) , thyroid cells (27) , intestinal cells (28 , 29) , bronchial epithelial cells, keratinocytes (30 , 31) , endothelial cells (32) , and fibroblasts (33) . Apart from its relevance in physiological circumstances such as mammary gland involution, postinflammatory capillary involution, and IEC physiology, loss of anchorage dependency is believed to be one of the key mechanisms leading to metastatic transformation of a neoplastic cell because it will enable a malignant cell to detach and spread from the primary tumor without undergoing anoikis (5 , 34, 35, 36, 37) .
Anoikis can be induced by loss of cell-matrix contact and/or loss of cell-cell contact (5 , 28 , 33 , 38, 39, 40, 41, 42) ; however, the molecular mechanisms initiating anoikis are still incompletely understood. FAK, an integrin-associated non-receptor kinase, seems to play a pivotal role transducing cell-matrix-mediated survival signals (43) . Loss of FAK signaling rather than caspase-mediated cleavage of FAK seems to induce activation of the apoptotic signaling cascade (38 , 43 , 44) . Caspase-9 can be activated due to cessation of protein kinase B/Akt-mediated phosphorylation (45) ; Akt is a downstream element of the phosphatidylinositol 3'-kinase (PI-3K) pathway, which plays a role in integrin/FAK-mediated survival signaling (46) . E-cadherins mediate cell-cell anchorage in IECs by homotypic zipper-like binding. Mutations or down-regulation of E-cadherin leads to anchorage independence and malignant transformation (47) , but the link between physiological E-cadherin signaling and inhibition of apoptosis is largely unknown. E-cadherin binding will lead to increased phosphorylation of proteins at sites of cell-cell contact (48) . However, phosphorylation of the E-cadherin-associated ß-catenin will promote its proteasome-mediated degradation, thereby blocking its interaction with transcriptional activators lymphocyte-enhancing factor 1 and T-cell factor 4 targeting genes such as c-myc (49) . The mechanisms leading to activation of the apoptotic cascade due to loss of cell-cell contact are unknown.
Some studies attribute a pivotal role to stress-activated protein kinases during anoikis signaling (50 , 51) , a finding that has not been confirmed by other investigators (52 , 53) . Recently, two groups concluded that anoikis is initiated via Fas-associated caspase-8 (54 , 55) , based on the observation that transfection of epithelial cell lines with dominant negative Fas-associated protein with death domain (FADD) was able to block anoikis.
In extension of our previous work on anoikis (29 , 56) , a comprehensive study on apoptotic signaling events during anoikis, such as long-prodomain caspase activation, mitochondrial cytochrome c release, intracellular translocation of caspases, and induction of DNA fragmentation, is presented, thereby describing additional characteristics of the anoikis pathway. In nontransformed primary human IECs, anoikis involves a highly ordered sequence of apoptotic signaling events initiated by the activation of procaspase-2 and -9 and followed by cytochrome c release and activation of caspase-8, which is clearly not the initial caspase to be activated during IEC anoikis.
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Results |
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TOPAbstractIntroductionResultsDiscussionMaterials and MethodsReferences |
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A total of 97 ± 2% of primary cells harvested stained positive for the epithelial cell marker EP-4 (Fig. 1A)
, whereas hardly any cells stained positive for CD3 (1 ± 0.5%, Fig. 1B
) or CD33 (1 ± 0.5%, Fig. 1C
), demonstrating that our protocol ensured isolation of highly purified IECs. Isotope control staining was negative (Fig. 1D)
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. To quantify this observation, we measured caspase-3-like activity at identical times. IECs of different regions along the crypt-villus axis showed no difference in caspase-3-like activity (Fig. 3B)
. These findings demonstrate that freshly detached primary human IECs are equipped to execute massive programmed cell death within 3 h. Nontransformed human IECs are genuinely susceptible to the induction of anoikis independently of their state of differentiation or proliferation.
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that caspase-2 is activated within 15 min of isolation (initiation of anoikis) because the prodomain is rapidly cleaved off, and the p16 subunit of caspase-2 becomes detectable. Caspase-9 also undergoes rapid processing within 15 min of detachment as the prodomain is lost, yielding the p37 intermediate that is rapidly further processed to yield the p10 subunit depicting the fully activated caspase within 30 min of detachment. Interestingly, caspase-8 remains initially inactivated (Fig. 5)
; however, after 30 min, the prodomain of caspase-8 is processed, and at 45–60 min after loss of cell anchorage, the p16 subunit indicative of activated caspase-8 is detectable.
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Anoikis Involves the Release of Cytochrome c from Mitochondria.
Release of cytochrome c in conjunction with loss of mitochondrial membrane potential has been described for distinct cell types and certain forms as the initiating event of apoptosis (17
, 18) . However, the role of mitochondrial cytochrome c release, which is also thought to serve as an intracellular augmentation factor of apoptosis (23)
, in anoikis is unknown. Therefore, primary human IECs were lysed without sonication using a weak detergent facilitating the separation of distinct intracellular compartments by centrifugation. As shown in Fig. 6A
, cytochrome c is indeed released into the cytosol as primary human IECs undergo anoikis. Whereas minimal cytochrome c is released before 30 min of the cascade, there is a massive cytochrome c release after 60 min of anoikis. Equal loading of cytosolic samples was demonstrated by reprobing the identical gel for actin. Negative staining of cytosol for cytochrome c oxidase subunit IV demonstrated a lack of contamination by mitochondria. Mitochondria showed staining for cytochrome c at any time during the apoptotic cascade (data not shown), and staining for cytochrome c oxidase subunit IV was positive, assuring that purification of mitochondria was successful (Fig. 6B)
. These data demonstrate that the execution of IEC anoikis involves the release of cytochrome c from mitochondria. Because only trace amounts of cytochrome c are released during the initiation phase, followed by massive release during the execution phase, it is unlikely that cytochrome c release plays a major role during the initiation of anoikis, but it is rather an important element of the downstream cascade, augmenting apoptotic signaling.
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After 90 min, activated caspase-3 can be detected predominantly in nuclei or evolving nuclear fragments (Fig 7)
. These findings confirm that caspase-3 is also activated during IEC anoikis and undergoes translocation as the apoptotic cascade proceeds, shifting from a predominant cytosolic localization to the nucleus of the dying enterocyte.
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demonstrates that caspase-6 activation occurs late during the apoptotic cascade as the p17 subunit becomes detectable after 60–90 min of anoikis.
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Discussion |
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TOPAbstractIntroductionResultsDiscussionMaterials and MethodsReferences |
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Given its physiological as well as pathophysiological relevance, research on the molecular mechanisms mediating anoikis will enhance our understanding of epithelial cell physiology and may depict new avenues to fight neoplasia.
The focus of this study was to delineate the intracellular cascade of initiating apoptotic signaling events during anoikis with special reference to the caspase cascade. We have developed a novel model, isolating highly purified nontransformed human IECs to pursue these studies in so-called "primary" cells. What conclusions can be drawn from this study, and how do they enhance our understanding of IEC biology, anoikis, and apoptosis?
The time course of anoikis in these primary IECs is striking, and, to our knowledge, few cells will execute apoptosis with similar kinetics. IECs are obviously equipped to instantly execute anoikis. On loss of anchorage, IECs will immediately activate caspases and execute apoptosis in essentially all IECs to the level of DNA fragmentation within 3 h. These data may reflect a characteristic of primary IECs because anoikis of transformed cell lines or cells with a slower physiological turnover takes several hours (5 , 41) or days (25 , 32 , 33) before detachment-induced programmed cell death is executed. All caspases tested are preformed within IECs and abundantly expressed, and their activation during anoikis does not require de novo protein synthesis (5 , 29) .
Given the stronger expression of antiapoptotic bcl-2 family members in IECs at the base of the intestinal crypt, our finding that these cells are just as sensitive to anoikis as those close to the region of shedding seems somewhat surprising; however, it may reflect that loss of cell anchorage is an inevitable death signal, incompatible with life for any nontransformed IECs.
The data presented give new insight into the molecular events during the initiation phase of the anoikis signaling cascade. Our findings cannot confirm the assumption drawn by other investigators that long-prodomain caspases do not play a role during anoikis (59) . Indeed, two long-prodomain caspases, caspase-2 and 9, are activated within 15 min of IEC anoikis, before the massive release of cytochrome c from the IEC mitochondria. These data demonstrate that anoikis follows a cascade similar to that of death receptor-mediated apoptosis rather than a pattern seen in chemically and radiation-induced apoptosis, where mitochondrial events occur upstream of caspase activation (17 , 18) . Seemingly in agreement with this assumption is the finding of two recent studies suggesting that caspase-8 may be the initial caspase activated via Fas-associated death domain during anoikis (54 , 55) . Indeed, caspase-8 is activated during IEC anoikis, but we could demonstrate by Western blot that caspase-8 is not the first caspase to be activated during anoikis in primary IECs. In contrast to the other reports, the antibody used in this study recognizes procaspase-8 as well as the p18 subunit indicative of the mature caspase. Our Western blots show that caspase-8 remains inactive during the initial 30 min, and the p18 subunit becomes detectable when 45–60 min have passed. Two explanations may account for these differences. First, IECs are isolated in our system within an intact crypt structure, and it takes about 15–30 min until the crypts and consequently the cell-cell contacts are fully disrupted. Therefore, as speculated by Frisch (54) , significant changes of IEC shape, possibly leading to "induced proximity" of death receptors and consecutive activation of caspase-8 (60) , may be delayed until cell-cell contact is lost. Second, the cascade of anoikis may vary between cell types or may reflect differences of intracellular signaling between immortalized cell lines and primary epithelial cells. During anoikis of IECs, caspase-8 activation is a downstream event, and our data suggest that it may reflect a positive feedback mechanism serving as an additional amplification loop.
Short-prodomain caspase-7, -3, and -6 are hierarchically activated during anoikis, with caspase-7 upstream of caspase-3 and caspase-6 activation. Indeed, caspase-6 is activated at the end of the cascade, a finding that does not confirm our previous observation (29) but demonstrates that activation of a specific caspase should not be assessed by any fluorogenic substrates but only by Western blot using antibodies that detect the proform and the subunits generated during activation. Cytochrome c is released from mitochondria during anoikis, presumably as an augmenting factor during the execution phase, when massive amounts are released, whereas the trace amounts of cytochrome c that can be detected eary during anoikis are unlikely to initiate anoikis. Indeed, the previously shown surge in caspase activity (29) is cotemporal with the massive release of cytochrome c. Finally, this study contributes to the understanding of caspase trafficking within a cell during apoptosis. In agreement with the observations of Chandler et al. (61) , caspase-3 initially shows a strong cytosolic activation pattern but displays a shift to the nucleus and its remnants during later stages of the apoptotic cascade.
In summary, this work further describes the sequence of intracellular events during anoikis, a physiological form of apoptosis, in a population of primary epithelial cells. Whereas our studies follow the caspase cascade upstream, the initiating event leading to the activation of caspase-2 is still unknown and is being addressed in ongoing studies. However, the data presented delineate the presumptive "default" cascade of apoptotic signaling during anoikis of primary cells (Fig. 10)
. To our knowledge, this work contributes to the few studies describing an apoptotic cascade in nontransformed human cells. Future studies on malignant and premalignant primary IECs are underway that might delineate the steps of the anoikis cascade at which alterations have occurred, rendering these cells anchorage independent and possibly leading to neoplastic and metastatic transformation.
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Materials and Methods |
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TOPAbstractIntroductionResultsDiscussionMaterials and MethodsReferences |
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To analyze IECs of different regions along the crypt-lumen axis in another set of experiments, sequential dispase incubations were undertaken as described previously (57) . Briefly, mucosal strips were incubated with dispase (1.2 units/ml) at 37°C. After 10, 20, and 30 min, IECs were extracted from the mucosal strip by vortex shaker (5 s), yielding epithelial cells of the upper, middle, and lower region of the intestinal crypt. Isolated IECs were washed in cold HBSS and resuspended in medium.
Flow Cytometry.
Because IECs are isolated as intact crypts using the protocol described above, single cell flow cytometry cannot be performed without further treatment of IECs to generate single cells. IECs harvested at indicated time points were therefore incubated for 2 min at 37°C with dispase (1.2 mg/ml; Boehringer Mannheim, Mannheim, Germany) followed by five vigorous shakes to fully disrupt cell-cell contacts. Enzyme activity was stopped by the addition of cold (4°C) EDTA (1 mM), and cells were washed twice in HBSS at 4°C. Cells were resuspended in 70% ice-cold methanol and stored at -20°C until analysis within 24 h. Flow cytometry analysis was performed according to standard technique (62)
. Briefly, fixed cells were washed twice in PBS, treated with RNase (1.0 mg/ml; Boehringer Mannheim) for 30 min at 37°C, stained with 50 µg/ml PI (Sigma, St. Louis, MO), and kept in the dark on ice for 30 min before analysis. PI-stained cells were measured on a Coulter Elite XL cytometer (Beckman Coulter, Fullerton, CA) at 488 nm excitation. A 630 nm long pass filter was applied to the red fluorescence of PI.(FL3). A minimum of 5 x 103 cells were measured per sample, and gating was applied on the sidescatter count to exclude debris and on the pulse width count to exclude remaining cell aggregates from analysis. To assess purity, methanol-fixed cells were washed twice in PBS followed by blocking (20 min, PBS/2% FCS). Each batch of cells was incubated with isotype control (mouse IgG1-FITC; Coulter Immunotech Diagnostic, Hamburg, Germany), Ber-EP-4 (Dako Diagnostika GmbH, Hamburg, Germany), anti-CD3 (Coulter Immunotech), and anti-CD33 (Coulter Immunotech).
Caspase Activity Assay.
Caspase-3-like activity was determined using the synthetic tetrapeptide substrate N-acetyl-Asp-Glu-Val-Asp-7-amino-4-methylcoumarin (DEVD AMC; Biomol, Plymouth Meeting, PA) as described previously (63)
. Briefly, 20 µg of IEC cytosol were incubated with 50 µM N-acetyl-Asp-Glu-Val-Asp-7-amino-4-methylcoumarin for 30 min at 37°C, and release of fluorescence reflecting caspase-3-like activity was quantified by fluorometry as described previously (29)
.
Western Blot.
IEC cytosol was extracted as described at different time points after loss of cell anchorage, and Western blot was performed as described previously (29)
. The following primary antibodies were used: anti-caspase-9 (1:5000) and anti-caspase-2 (1:3000; both kindly provided by Sophie Roy; MerckFrost Pharmaceuticals, Quebec, Canada), anti-caspase-6 (1:3000; Becton Dickinson), DFF (1:1000; (Becton Dickinson). For Western blot studies on cytochrome c (anti-cytochrome c; 1:5000; Becton Dickinson), cells were lysed without sonication using digitonin as detergent as described previously (64)
. Mitochondria were isolated as described after cell lysis, and purity of the mitochondrial cell fraction was confirmed by probing for the mitochondrial enzyme cytochrome c oxidase IV, subunit II [1:5000; Mobitec, Göttingen, Germany (64
, 65)
]. Equal loading of the cytosolic samples was demonstrated by reprobing membranes with anti-actin (1:10000; Chemicon, Hofheim, Germany).
Immunocytochemistry.
Ex vivo isolated human IECs were kept in suspension, and aliquots were taken at the indicated times. After cytospin (3 min at 300rpm), fixation and permeabilization were performed ("fix and perm" kit; An der Grube Bio Research GmbH, Kaumberg, Austria). Cells were then incubated with blocking buffer (2% BSA, 0.2% fat-free milk, 2% normal goat serum, and 0.8% Triton X-100 in PBS) followed by incubation with primary anti caspase-3 antibodies (CM-1 at 1:7500; kindly provided by IDUN Pharmaceuticals, La Jolla, CA) or isotope control for 1 h at ambient temperature. After washings in PBS, incubation with secondary biotinylated goat antirabbit antibody (Vectastain kit; Vector Laboratories, Burlingame, CA) for 1 h, and 1 h of incubation with avidin-biotin-peroxidase complex at ambient temperature, peroxidase substrate (3.3'-diaminobenzidine; Sigma) was added for 20 s, and the reaction was stopped by two washings in PBS.
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Acknowledgments |
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Footnotes |
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1 Supported by ReForM A and ReForM B (Medical Research Funding Program of the University of Regensburg, Regensburg, Germany) grants (to J. G.) and Grants GR1523/1-1, GR 1523/1-2, and GR1523/3-1 from the Deutsche Forschungsgemeinschaft, Bonn, Germany (to J. G.). 
2 To whom requests for reprints should be addressed, at Department of Medicine I, University of Regensburg, Franz-Josef-Strasse-Allee 11, 93042 Regensburg, Germany. Phone: 49-941-944-7001; Fax: 49-941-944-7002; E-mail: Johannes.Grossmann{at}klinik.uni-regensburg.de
3 The abbreviations used are: IEC, intestinal epithelial cell; FAK, focal adhesion kinase; PI, propidium iodide; DFF, DNA fragmentation factor.
Received for publication 9/11/01. Revision received 1/ 8/01. Accepted for publication 1/ 8/01.
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References |
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