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Experimental Therapeutics, Molecular Targets, and Chemical Biology |
Cancer Therapeutics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland
Requests for reprints: Phillip A. Dennis, National Cancer Institute/Navy Medical Oncology, Room 5101, Building 8, 8901 Wisconsin Avenue, Bethesda, MD 20889. Phone: 301-496-0929; Fax: 301-496-0047; E-mail: pdennis{at}nih.gov.
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Abstract |
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Introduction |
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15% to 20% of all lung cancer cases in the United States and is typically characterized by initial therapeutic responsiveness followed by disease recurrence that is much more aggressive in nature and chemotherapeutically resistant (1). Over the last 20 years, only incremental improvement in survival has been noted with chemotherapy in SCLC, which has prompted clinical evaluation of more "targeted" drugs such as imatinib (2). Whereas the mechanisms by which SCLC cells acquire the ability to evade chemotherapy-induced death is unclear, composition of the tumor microenvironment, specifically extracellular matrix (ECM) composition, may play a role (3, 4).
ECM is composed of protein polymers that are organized into a meshwork (5). Cell adhesion to the ECM is mediated through the integrin family of heterodimeric transmembrane receptors, which are composed of 
and ß subunits (6). Most transformed cells (including most SCLC cell lines) have developed the ability to survive and proliferate in the absence of cell adhesion (7). Interestingly, SCLC cells in vivo are surrounded by a dense stroma of ECM at primary and metastatic sites (4). Adhesion of SCLC cells to ECM proteins in vitro confers resistance to chemotherapy-induced apoptosis that is dependent on protein tyrosine kinase activity (4). These data suggest that adhesion-dependent activation of signaling pathways may contribute to chemotherapeutic resistance in SCLC.
Of the pathways activated by integrin-ECM binding, the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) and mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (MEK/ERK) pathways are essential for integrin-mediated regulation of cell proliferation and survival (8, 9). Both pathways play key roles in tumorigenesis and therapeutic resistance (10, 11). Inhibition of the PI3K/Akt pathway sensitizes non-SCLC (NSCLC) or SCLC cells to traditional chemotherapeutic agents (12, 13). In addition, adherent SCLC cells that are selected after prolonged subculturing show increased activation of Akt and ERK and greater resistance to traditional chemotherapy or radiation (14). Enhanced survival of SCLC cells on physiologic ECM proteins may therefore be due to adhesion-dependent activation of the PI3K/Akt/mTOR and/or MEK/ERK pathways.
Here we report that SCLC cell lines differentially activate Akt and ERK activity after adhesion to specific ECM components. Adhesion to laminin increased Akt activity, altered cell morphology, and promoted resistance to serum withdrawal-induced cell death. Inhibitors of the PI3K/Akt/mTOR pathway but not MEK/ERK pathway abrogated laminin-mediated survival. Although SCLC cells adherent to laminin were unaffected by the addition of imatinib, biochemical or genetic inhibition of the PI3K/Akt/mTOR pathway induced responsiveness to imatinib, as well as traditional chemotherapies. These results suggest that adhesion-dependent activation of the PI3K/Akt/mTOR pathway may be one of the factors involved in the survival and chemotherapeutic resistance of SCLC. Targeting this pathway may be a useful approach to improve the therapeutic responsiveness of SCLC cells.
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Materials and Methods |
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Reagents. Phospho-specific antibodies directed against Ser473 (S473) of Akt, Thr202 and Tyr204 (T202/Y204) of ERK-1/2, S389 of p70S6K, native antibodies against Akt, ERK-1/2, and p70S6K and antibodies against hemaglutinin, phospho-c-Kit (Y719), c-Kit, PDGFR, PDGFRß, and ß-galactosidase (ß-Gal) were purchased from Cell Signaling Technology (Beverly, MA). -Tubulin antibodies were obtained from Sigma-Aldrich (Milwaukee, WI). The ß1 integrin–activating antibody (TS2/16) was a gift of Dr. David Roberts (NIH, Bethesda, MD) and has been previously described (15). LY294002, rapamycin, and U0126 were purchased from Calbiochem EMD Biosciences, Inc. (La Jolla, CA). Imatinib was obtained from Novartis Pharmaceuticals Corp. (East Hanover, NJ). Six- and 12-well coated plates (laminin, fibronectin, and collagens I and IV) were purchased from Discovery Labware BD Biosciences (Bedford, MA). Stem cell factor (SCF) was purchased from Sigma-Aldrich, and platelet-derived growth factor (PDGF) was obtained from R&D Systems (Minneapolis, MN).
Extracellular matrix adhesion assays. All cell lines were plated on plastic or ECM-coated tissue culture plates (laminin, fibronectin, and collagens I and IV) in low-serum conditions and cultured for 5 days at 37°C, 7.5% CO2. After culturing, cells were harvested and processed for immunoblot analysis as described below. For time course experiments, H69, H209, H128, and H526 cells were plated on plastic or laminin-coated tissue culture plates in low-serum conditions and cultured for the indicated times followed by harvesting and processing for immunoblot analysis.
Stimulation with stem cell factor or platelet-derived growth factor. H69, H209, and H526 were serum starved overnight on 6-well plates in RPMI 1640 with low-serum conditions, and 50 ng/mL SCF or 100 ng/mL PDGF-AB were added 10 minutes before harvest. In the combinatory treatment with imatinib, the cells were pretreated with imatinib for 30 minutes before administration with SCF.
Apoptosis. For apoptosis experiments, H69 and H209 cells were plated on plastic or laminin-coated tissue culture plates in low-serum conditions and cultured for 3 days at 37°C, 7.5% CO2. Following adhesion, cells were treated or not with LY294002, rapamycin, or U0126 in the presence or absence of imatinib, and the cells were cultured for an additional 72 hours. After the total culture time (6 days), cells were harvested and processed for flow cytometric analysis of apoptosis, as assessed by formation of subgenomic DNA fragmentation (12).
Adenoviral infection of H69 cells. H69 cells were plated on plastic or laminin-coated tissue culture plates in low-serum conditions and cultured for 2 days at 37°C, 7.5% CO2. The cells were then infected with adenoviral particles encoding either the adenoviral-encoded ßGal gene (Ad-ßGal) or adenoviral-encoded dominant-negative Akt (Ad-dnAkt) for 24 hours. (These adenoviruses were kind gifts of Dr. Kenneth Walsh, Boston, MA). Following the infection period, the cells were treated or not with imatinib for 72 hours, after which the cells were harvested and processed for flow cytometric and immunoblot analysis as previously described (12).
Immunoblotting. Cell extracts were prepared for SDS-PAGE and immunoblot analysis as previously described (12).
Statistical analysis. Statistical comparison of mean values was done using the Student's t test. All P values are two tailed.
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Results |
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The MEK/ERK cascade promotes the survival of NSCLC cells and can be activated in response to cell adhesion (17). We therefore assessed activation of the MEK/ERK pathway in SCLC cell lines in response to ECM adhesion by monitoring the phosphorylation of ERK. Under high-serum conditions (Fig. 1C, left), H69 cells increased ERK phosphorylation on laminin and collagen IV, whereas H345 cells showed increased ERK phosphorylation on laminin and collagens I and IV. Under low-serum conditions (Fig. 1C, right), H69 cells only increased ERK activation when plated on laminin, whereas H345 cells did not activate ERK on any ECM protein. Levels of ERK phosphorylation were below baseline when H345 cells were plated on fibronectin or collagens I or IV. Interestingly, whereas the H510 cell line showed constitutive ERK activity when grown on plastic, these cells did not increase ERK activation on any matrix under either high- or low-serum conditions. Laminin or fibronectin inhibited ERK activation in these cells. Taken together, these data show that Akt and ERK are activated in SCLC cells in a cell line– and ECM-specific manner. Because laminin consistently increased Akt and ERK activation in H69 cells, adhesion of these cells to laminin was explored further.
Adhesion of small cell lung cancer cells to laminin increases Akt and extracellular signal-regulated kinase activation and increases cell survival and alters cell morphology. To assess the time dependence of activation of Akt and ERK and to assess cellular behavior after adhesion to laminin, we assessed parallel samples on days 1, 3, and 5 for immunoblotting, flow cytometry, and phase-contrast microscopy. On day 1, phosphorylation of ERK but not Akt was increased in cells plated on laminin (Fig. 2A, top left). On days 3 and 5, the activation of Akt and ERK was increased in cells on laminin compared with plastic. Maximal activation of Akt and ERK was observed on day 5.
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To generalize these observations, we characterized three additional SCLC cell lines. H209, H128, and H526 cells were grown on plastic or laminin under low-serum conditions, and time-dependent activation of signaling pathways on laminin or plastic was assessed. In H209 and H526 cells (Fig. 2B, top and middle, respectively), phosphorylation of Akt was increased on laminin on days 3 and 5. In H128 cells (Fig. 2B, bottom), basal levels of Akt phosphorylation were high on plastic or laminin and did not differ during the course of the experiment (Fig. 2B, top and middle). Phosphorylation of ERK diminished with time in H209 and H526 cells but was maintained to a greater extent in cells plated on laminin (Fig. 2B, top and middle). In H128 cells, phosphorylation of ERK was increased on laminin on days 3 and 5 (Fig. 2B, bottom). Similar induction of Akt activation on laminin was also observed in H209 and H526 cells when they were grown in medium containing 10% FBS (data not shown). These results suggest that laminin-stimulated activation of the PI3K/Akt or MEK/ERK pathway is a common event in the SCLC cells.
Cell adhesion to the ECM protein laminin has been shown to be mediated by ß1-containing integrin receptors in other cell types (18). To determine if ß1 integrin receptors were involved in the laminin adhesion–dependent activation of Akt in H69 cells, we evaluated activation of Akt and ERK in response to ß1-activating antibodies when cells were plated on plastic (Fig. 2C). These antibodies have been previously shown to specifically induce ß1 activity (15). Whereas no difference in Akt activation between ß1- and control-treated H69 cells was observed on day 1, increased activation of Akt in response to ß1 activating antibodies compared with control IgG was observed on day 3. By day 5, Akt activity decreased below baseline for both conditions. Compared with control IgG, ERK activation was dramatically increased at day 1 in response to the ß1-activating antibody. On days 3 and 5, however, control IgG nonspecifically increased ERK phosphorylation, which limits interpretation of these results. Nonetheless, these results show that activation of Akt and ERK is increased in a time-dependent manner in response to SCLC cell adhesion to laminin, and this is partially recapitulated by treating SCLC cells on plastic with ß1 integrin–activating antibodies.
Inhibition of the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin pathway but not mitogen-activated protein kinase kinase/extracellular signal-regulated kinase pathway attenuates laminin-mediated protection of small cell lung cancer cells and induces responsiveness to imatinib. To evaluate the contribution of the PI3K/Akt/mTOR or MEK/ERK pathways to laminin-mediated survival, the ability of kinase inhibitors to decrease protection conferred by laminin was assessed. The targets of LY294002, rapamycin, and U0126 (PI3K, mTOR, and MEK, respectively) are shown in the pathway diagram (Fig. 3, left). H69 cells plated on laminin were less susceptible to serum withdrawal–induced apoptosis than those plated on plastic. The addition of a PI3K inhibitor, LY294002, to H69 cells plated on laminin reversed the protective effect of laminin and returned levels of apoptosis to that observed on plastic alone (Fig. 3, top left). Treatment with an mTOR inhibitor, rapamycin, also attenuated the protective effect of laminin; however, not to the same extent as was observed with LY294002 (Fig. 3, top right). The combination of LY294002 and rapamycin abrogated the protection conferred by laminin and increased the level of apoptosis to above what was seen in cells plated on plastic (Fig. 3, bottom left). In contrast, the MEK inhibitor, U0126, not only failed to attenuate the protective effect of laminin but also increased the protective effects of laminin (Fig. 3, bottom right). The basis for this protection is unclear. Taken together, these results show that inhibition of the PI3K/Akt/mTOR pathway but not the MEK/ERK pathway is capable of reversing the protective effect of laminin on SCLC cells.
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, and PDGFRß are expressed in the SCLC cell lines used in our studies (Fig. 4A). c-Kit was expressed in all SCLC cell lines, with the lowest levels observed in the H69 cells and the highest levels observed in the H209 and H526 cells. In contrast, PDGFR or PDGFRß was not expressed in any SCLC cell line tested but was expressed in NIH3T3 cells, which are known to express PDGFR and PDGFRß.
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The relationship between laminin-induced activation of signaling pathways and apoptotic response to imatinib was examined next. H69 cells that are plated on plastic undergo apoptosis when exposed to imatinib (data not shown; ref. 21). However, when H69 cells were plated on laminin, the addition of imatinib did not induce apoptosis (Fig. 5A). In fact, imatinib decreased serum starvation induced apoptosis, although this did not reach statistical significance in all experiments. When LY294002 was added to cells plated on laminin, apoptosis increased, and when LY294002 and imatinib were added in combination, cells were sensitized to imatinib-mediated apoptosis (Fig. 5A, top left). Similar results were observed with rapamycin alone or LY294002 and rapamycin in combination (top right and bottom left, respectively). Apoptosis increased with these inhibitors without imatinib. In the presence of imatinib, additional increases in apoptosis were observed. If the decreased levels of apoptosis observed with imatinib alone are taken into account, combining LY294002, rapamycin, or LY294002 and rapamycin with imatinib resulted in greater than additive increases in apoptosis of SCLC cells. The MEK inhibitor U0126 or imatinib alone decreased serum deprivation–induced apoptosis of laminin-adherent SCLC cells. When U0126 and imatinib were combined, the absolute level of apoptosis remained below that observed with untreated laminin-adherent cells (Fig. 5A, bottom left). Thus, inhibition of the PI3K/Akt/mTOR pathway but not the MEK/ERK pathway abrogates laminin-mediated protection of SCLC cells and increases responsiveness to imatinib.
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To extend these results, we treated H209 and H526 cells that were plated on laminin with imatinib and/or LY294002 or U0126 (Fig. 5C). Both cell lines adherent to laminin were resistant to imatinib. LY294002 alone increased apoptosis in H209 cells but not H526 cells. Nevertheless, combining LY294002 with imatinib significantly increased apoptosis in both SCLC cell lines. U0126 alone was protective in H209 cells and had no effect in H526 cells, and the combination of imatinib plus U0126 yielded similar results to that observed with U0126 alone in each cell line. These data support our results with H69 cells in that inhibition of the PI3K/Akt/mTOR pathway but not MEK/ERK pathway sensitizes SCLC cells to imatinib.
To further establish the role of the PI3K/Akt/mTOR pathway in mediating protection of SCLC cells caused by adhesion to laminin, SCLC cells plated on laminin were infected with Ad-dnAkt or Ad-ßGal, and apoptosis was assessed in the absence or presence of imatinib under low-serum conditions (Fig. 5D). Similar to results observed with LY294002, adenoviral-mediated overexpression of dominant-negative Akt in laminin-adherent H69 cells increased apoptosis. Combining imatinib with Ad-dnAkt resulted in greater than additive increases in apoptosis. These results support the data using small-molecule kinase inhibitors and suggest that inhibition of the PI3K/Akt/mTOR pathway at multiple points can attenuate laminin-mediated protection and induce sensitivity to imatinib.
Inhibition of the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin pathway but not mitogen-activated protein kinase kinase/extracellular signal-regulated kinase pathway increases responsiveness of laminin-adherent small cell lung cancer cells to traditional chemotherapies. To determine whether laminin-mediated activation of the PI3K/Akt/mTOR pathway could confer resistance to other therapies used in SCLC, we treated H69 and H209 cells plated on laminin with cisplatin or etoposide in the absence or presence of LY294002 or U0126 (Fig. 6). In each cell line, LY294002 significantly increased apoptosis induced by cisplatin or etoposide. Interestingly, U0126 significantly reduced apoptosis induced by cisplatin but did not significantly change apoptosis induced by etoposide. These findings are consistent with our data with imatinib and indicate that the PI3K/Akt/mTOR pathway plays a generalized role in laminin-mediated drug resistance in SCLC cells. Moreover, they suggest that combining inhibition of the PI3K/Akt/mTOR pathway with chemotherapy or targeted agents such as imatinib may overcome resistance conferred by ECM components such as laminin.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Adhesion to the ECM profoundly affects the behavior of SCLC cells in vitro and in vivo. We showed that the adhesion of H69, H345, H510, and H526 cells to the ECM protein laminin causes dramatic alterations in cell morphology concomitant with increased cell survival in the absence of serum. In addition, we showed that this adhesion is likely mediated by ß1-containing integrin receptors. The change in cell shape we observed is characteristic of the reacquisition of an adherent, epithelial-type morphology that has been described in histologically variant tumor cells within SCLC (25, 26). These cells are highly prevalent in sites of SCLC metastasis (27). Sethi et al. have previously reported that adhesion-mediated alterations in SCLC cell morphology are dependent on ß1 integrin activity (4), but our data show that adhesion to laminin confers resistance to serum withdrawal–induced cell death. This might be relevant because before the recruitment of a vascular supply, tumor cells at secondary sites must be able to thrive under growth factor–deficient conditions (7), suggesting that the adhesion-mediated survival we observe may be important for the establishment of SCLC metastasis. In vivo, SCLC cells are surrounded by a dense meshwork of ECM proteins and the interaction of SCLC cell lines with ECM enhances invasiveness (3, 4). Moreover, increased expression of ß1 integrin is a poor prognostic factor for patients with SCLC (28).
How does adhesion to ECM and development of an adherent phenotype promote SCLC cell survival in the absence of growth factors? We showed that in H69, H345, H209, and H526 cells, adhesion to laminin increased activation of two serine/threonine kinases, Akt and ERK, which paralleled the morphologic change and protection from serum withdrawal–induced cell death. Biochemical or genetic inhibition of the PI3K/Akt/mTOR pathway reversed the protection conferred by laminin. In contrast, inhibition of the ERK pathway had no effect on the protective effects of laminin. Adhesion-mediated activation of Akt and ERK in H69 cells has been previously reported (14); however, increased signaling was in response to nonspecific adhesion not to a defined ECM component such as laminin. In addition, Sethi et al. showed that H69 ß1 integrin–dependent adhesion to the ECM protein fibronectin resulted in activation of protein tyrosine kinases (4), presumably due to integrin-mediated activation of receptor tyrosine kinases (RTK; ref. 29). The PI3K inhibitor LY294002 has also been shown to abolish SCF/SDF-induced Akt activity in H69 cells and thereby inhibit cellular adhesion (30). Together, these data suggest that the promotion of SCLC cellular survival and morphologic change by ECM relies on activation of the PI3K/Akt pathway.
ECM-mediated activation of the PI3K/Akt/mTOR pathway in SCLC cells promotes resistance to standard and novel therapeutic agents. Traditional agents have included doxorubicin, etoposide, and cisplatin, as well as radiation (4, 13, 14, 31, 32). Our study extends these observations and shows that SCLC cells adherent to laminin are resistant to traditional chemotherapies such as cisplatin and etoposide, as well as to the novel tyrosine kinase inhibitor imatinib.
Although imatinib is approved for the treatment of chronic myelogenous leukemia and gastrointestinal stromal tumors (33, 34), its activity in SCLC is limited. Imatinib inhibits the growth of SCLC cell lines in vitro (21, 35), but it has been ineffective at inhibiting tumor growth in preclinical models of human SCLC (36) as well as in a phase II SCLC clinical trial (20). A diagram linking adhesion to laminin, activation of c-Kit, activation of the PI3K/Akt/mTOR pathway, and the apoptotic response to imatinib is shown in Fig. 7. Imatinib has at least three targets, two of which are the RTKs, PDGFRs, and c-Kit. Coexpression of c-Kit and its ligand, SCF, has been shown in 70% of SCLC tumor specimens and several SCLC cell lines, including H69 cells (30, 37, 38). Surprisingly, the prognostic significance of c-Kit expression in SCLC patients is unsettled (39–41) perhaps because various methods have been used to measure c-Kit, or because the importance of c-Kit depends on the status of and interaction with other molecules such as components of the ECM or growth factor receptors. Expression of the other known target RTK for imatinib, PDGFRs, in SCLC cells was not observed in our study but may have greater importance in stromal cells. Moreover, other relevant unknown targets may exist for imatinib because imatinib can inhibit the growth of SCLC cells in vivo that do not express c-Kit or PDGFR (42).
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Acknowledgments |
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Footnotes |
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Received 1/ 7/05. Revised 6/15/05. Accepted 7/ 7/05.
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