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Tumor-Induced Apoptosis of T Cells: Amplification by a Mitochondrial Cascade1

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Tumor-Induced Apoptosis of T Cells: Amplification by a Mitochondrial Cascade1 [CANCER RESEARCH 60, 6811–6817, December 15, 2000] Advances in Brief Tumor-induced Apoptosis of T Cells: Amplification by a Mitochondrial Cascade1 Brian R. Gastman, Xiao-Ming Yin, Daniel E. Johnson, Eva Wieckowski, Gui-Qiang Wang, Simon C. Watkins, and Hannah Rabinowich2 Departments of Otolaryngology [B. R. G.], Pathology [X-M. Y., E. W., G-Q. W., H. R.], Pharmacology [D. E. J.], Medicine [D. E. J.], and Cell Biology and Physiology [S. C. W.], University of Pittsburgh School of Medicine and University of Pittsburgh Cancer Institute [X-M. Y., D. E. J., S. C. W., H. R.], Pittsburgh, Pennsylvania 15213 Abstract cysteine proteases, play critical roles in the execution phase of apo- ptosis and are responsible for many of the biochemical and morpho- We have recently reported that apoptosis of T cells induced by squa- logical changes associated with apoptosis (5–7). Caspase-8 has been mous cell carcinoma of the head and neck (SCCHN) is partly Fas depend- identified as the most apical caspase in apoptosis induced by several ent. This tumor-induced T-cell death is mediated by the activities of 3 caspase-8 and caspase-3 and is partially inhibited by antibodies to either death receptors, including Fas and TNFR1 (8). Fas-associated death Fas or Fas ligand. We report here that in contrast to apoptosis induced by domain is recruited directly to ligated Fas or indirectly to ligated agonistic anti-Fas antibody (Ab), the tumor-induced apoptotic cascade in TNFR1, resulting in recruitment and autoactivation of caspase-8. Jurkat cells is significantly amplified by a mitochondrial loop. The in- Active caspase-8 cleaves and activates downstream caspases, initiat- volvement of mitochondria in tumor-induced apoptosis of T cells was ing the caspase cascade. Caspase-9 has been proposed as the initiating demonstrated by changes in mitochondrial permeability transition as caspase in a pathway of apoptosis that is death receptor independent -assessed by 3,3؅-dihexiloxadicarbocyanine staining, by cleavage of cyto (9, 10). In the presence of dATP and cytochrome c, the long NH2- solic BID and its translocation to the mitochondria, by release of cyto- terminal domain of caspase-9 interacts with APAF-1, resulting in chrome c to the cytosol, and by the presence of active subunits of caspase-9 activation of caspase-9. Active caspase-9 can then activate the effector in Jurkat T cells cocultured with tumor cells. To further elucidate the caspase-3, -6, and -7 (10, 11). Thus, there are at least two major significance of mitochondria in tumor-induced T-cell death, we investi- gated the effects of various inhibitors of the mitochondrial pathway. mechanisms by which a caspase cascade may be initiated: (a) one Specific antioxidants, as well as two inhibitors of mitochondria perme- involving capase-8; and (b) the other involving caspase-9 as the most ability transition, bongkrekic acid and cyclosporin A, significantly apical caspase. blocked the DNA degradation induced in Jurkat T cells by SCCHN cells. These two basic pathways of caspase activation allow predictions However, these inhibitors had no effect on cells triggered by anti-Fas Ab. as to how the apoptotic cascade is regulated under different circum- Furthermore, a cell-permeable inhibitor of caspase-9, Ac-LEHD.CHO, stances. It is expected that various inhibitors of apoptosis, including which did not inhibit T-cell apoptosis induced by anti-Fas Ab, markedly Bcl-2 family members, CrmA, FLICE-inhibitory protein, or inhibitors inhibited apoptosis induced by etoposide or by coculture of Jurkat with of apoptosis, which target different caspases or intracellular apoptotic SCCHN cells. These findings demonstrate that apoptotic cascades induced events, will differentially regulate the two caspase activation cas- in Jurkat T lymphocytes by anti-Fas Ab or tumor cells are differentially susceptible to a panel of inhibitors of mitochondrial apoptotic events. It cades. For example, antiapoptotic Bcl-2 family members bind to appears that besides the Fas-mediated pathway, additional mitochondria- mitochondria and inhibit release of cytochrome c (12, 13). Therefore, dependent cascades are involved in apoptosis of tumor-associated lym- apoptotic signaling via death receptors should be resistant to Bcl-2 phocytes. Inhibition of mitochondria-dependent cascades of caspase acti- (14). However, it seems that Bcl-2 and Bcl-xL can also interfere with vation should be considered to enhance the success of immunotherapy or Fas-mediated apoptosis in cells in which the Fas/Fas-associated death vaccination protocols in cancer. domain/procaspase-8 recruitment is not efficient (15). Because Fas ligation is associated with release of cytochrome c, it raises the Introduction possibility of cross-talk between the two basic pathways. Recently a mechanism of cross-talk between caspase-8 and caspase-9 via mito- Recent studies suggest that human carcinoma cells of various chondria was identified (9, 16, 17). BID, a proapoptotic member of origins can activate intrinsic programmed cell death in lymphocytes the Bcl-2 family, is cleaved by caspase-8, and its COOH-terminal interacting with the tumor in situ and in vitro (1–3). This tumor- fragment translocates to the mitochondria and triggers release of induced apoptosis of lymphocytes may have important implications cytochrome c (9, 16, 17). Depletion of BID from cytosolic extracts for the success of therapeutic regimens, including vaccination strate- disrupts the ability of caspase-8 to trigger cytochrome c release in gies (4). Because tumor-induced apoptosis of lymphocytes may be vitro (17). mediated by an array of death receptors coexpressed on T cells or by The current study investigated intracellular apoptotic events in tumor-derived soluble factors, it is important to characterize those Jurkat T cells interacting with SCCHN. The intracellular effector intracellular events that may be potential targets for therapeutic inter- molecules involved in execution of tumor-induced death of lympho- vention to minimize T-cell apoptosis. The caspases, a family of cytes, which might serve as potential targets for inhibition of apo- ptosis, have not yet been elucidated. Our recent studies (18, 19) Received 5/17/00; accepted 10/25/00. The costs of publication of this article were defrayed in part by the payment of page demonstrated that apoptosis induced in T lymphocytes by tumor cells charges. This article must therefore be hereby marked advertisement in accordance with was, in part, Fas mediated and involved activation of caspase-8 and -3. 18 U.S.C. Section 1734 solely to indicate this fact. 1 Supported by NIH Grants RO1 CA 84134-01 (to H. R.) and PO1DE 12321-01 (to H. R.), a grant from The Pittsburgh Foundation (to H. R.), American Cancer Society Grant 3 The abbreviations used are: TNFR, tumor necrosis factor receptor; BA, bongkrekic RPG-98-288-01-CIM (to H. R.), Department of Defense Grant BC981056 (to H. R.), a acid; CsA, cyclosporin A; DiOC6(3), 3,3Ј-dihexiloxadicarbocyanine; ROS, reactive ox- grant from the Pennsylvania Department of Health (to H. R.), and Cell and Tissue Imaging ygen species; SCCHN, squamous cell carcinoma of the head and neck; Ab, antibody; Facility Grant 2P30-CA-47904 (to S. C. W.). CMXRos, chloromethyl-X-rosamine; GAMIg, goat antimouse immunoglobulin; DPI, 2 To whom requests for reprints should be addressed, at University of Pittsburgh diphenyleneiodonium chloride; NAC, N-acetyl-L-cysteine; mAb, monoclonal Ab; dThd, Cancer Institute, W952 Biomedical Science Tower, 200 Lothrop Street, Pittsburgh, PA thymidine; HM, heavy membrane; PT, permeability transition; ANT, adenine nucleotide 15213. Phone: (412) 624-0289; Fax: (412) 624-7737; E-mail: rabinowϩ@pitt.edu. translocator. 6811 Downloaded from cancerres.aacrjournals.org on September 30, 2021. © 2000 American Association for Cancer Research. TUMOR-INDUCED MITOCHONDRIAL APOPTOTIC CASCADE IN T LYMPHOCYTES In the present study, we investigated the role of a mitochondrial DiOC6(3) (40 nM, 15 min at 37°C) and then stained without fixation by cascade and its significance in SCCHN-induced apoptosis of Jurkat T phycoerythrin-conjugated anti-CD3 Ab. CD3ϩ cells were gated to assess lymphocytes. Our findings suggest that in contrast to Fas-mediated mitochondrial staining by DiOC6(3). apoptosis of Jurkat cells, which is mitochondria independent, mito- Subcellular Fractionation. After induction of apoptosis, Jurkat cells were chondria have a significant effector role in tumor-induced cell death harvested in isotonic mitochondrial buffer (20 mM sucrose, 20 mM HEPES, 10 mM KCl, 1.5 mM MgCl ,1mM EDTA, 1 mM EGTA, 1 mM DTT, 10 ␮g/ml of interacting T cells. 2 leupeptin, 1 mM phenylmethylsulfonyl fluoride, and 10 ␮g/ml aprotinin) and Materials and Methods Dounce homogenized by 15–20 strokes. Samples were transferred to Eppen- dorf centrifuge tubes and centrifuged at 500 ϫ g for 5 min at 4°C to eliminate Reagents. Agonistic anti-Fas Ab (CH-11; IgM) was purchased from Up- nuclei and unbroken cells. The resulting supernatant was centrifuged at state Biotechnology (Lake Placid, NY), rabbit anti-caspase-9 Ab (clone H-83) 10,000 ϫ g for 30 min at 4°C to obtain the HM pellet. The supernatant was was from Santa Cruz Biotechnology (Santa Cruz, CA), anti-cytochrome c was further centrifuged at 100,000 ϫ g for1hat4°Ctoyield the final soluble from PharMingen (San Diego, CA), and anti-cytochrome c oxidase was from cytosolic fraction, S100. HM and S100 subcellular fractions were assessed for Molecular Probes (Eugene, OR). Rabbit anti-BID polyclonal Ab used has been the presence of cytochrome c or cytochrome c oxidase by Western blot described previously (20). The caspase-9 inhibitor, Ac-LEHD.CHO, was pur- analyses. chased from NovaBiochem (San Diego, CA), DiOC6(3) and CMXRos were Analysis of Protein Expression by Western Blotting. After apoptosis- from Molecular Probes, and GAMIg-conjugated magnetic beads were from inducing treatment, cells were washed and lysed in lysis buffer [1% NP40, 20 PerSeptive Diagnostics (Cambridge, MA).
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