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A Tumor Suppressor Function for Caspase-2

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A Tumor Suppressor Function for Caspase-2 A tumor suppressor function for caspase-2 Lien Ha Hoa, Robyn Taylora, Loretta Dorstyna, Dimitrios Cakourosa, Philippe Bouilletb, and Sharad Kumara,1 aCentre for Cancer Biology, Hanson Institute, Frome Road, Adelaide, SA 5000, Australia; and bThe Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3050, Australia Edited by Jerry M. Adams, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, and approved February 6, 2009 (received for review November 23, 2008) Apoptosis is mediated by the caspase family of proteases that act as hypothesis using in vitro and in vivo approaches, and we provide effectors of cell death by cleaving many cellular substrates. Caspase-2 evidence that caspase-2 is a tumor suppressor. is one of the most evolutionarily conserved caspases, yet its physio- logical function has remained enigmatic because caspase-2-deficient Results mice develop normally and are viable. We report here that the Growth Properties of caspase-2؊/؊ MEFs. We analyzed the growth caspase-2؊/؊ mouse embryonic fibroblasts (MEFs) show increased properties of caspase-2ϩ/ϩ and caspase-2Ϫ/Ϫ MEFs and consistently proliferation. When transformed with E1A and Ras oncogenes, found that caspase-2Ϫ/Ϫ MEFs had a significantly higher growth caspase-2؊/؊ MEFs grew significantly faster than caspase-2؉/؉ MEFs rate compared with caspase-2ϩ/ϩ MEFs (Fig. 1A). Although the and formed more aggressive and accelerated tumors in nude mice. To data shown in Fig. 1A is derived from 3 different batches of cells assess whether the loss of caspase-2 predisposes animals to tumor from 3 animals of each genotype, we have tested at least 8 batches development, we used the mouse E␮-Myc lymphoma model. Our of cells from 8 independent embryos per genotype, all showing findings suggest that loss of even a single allele of caspase-2 resulted similar results (data not shown). To avoid potential selection of cells in accelerated tumorigenesis, and this was further enhanced in with higher growth rates, in most of our experiments, MEFs at -caspase-2؊/؊ mice. The caspase-2؊/؊ cells showed resistance to apo- passages 2–4 were used. We noted that following replating caspase ptosis induced by chemotherapeutic drugs and DNA damage. Fur- 2Ϫ/Ϫ MEFs appeared to require a somewhat longer recovery period thermore, caspase-2؊/؊ MEFs had a defective apoptotic response to than the matched caspase-2ϩ/ϩ MEFs. We then tested whether cell-cycle checkpoint regulation and showed abnormal cycling follow- increased growth rate of caspase-2Ϫ/Ϫ cells leads to their transfor- ing ␥-irradiation. These data show that loss of caspase-2 results in an mation, by analyzing their ability to form colonies in soft agar. We increased ability of cells to acquire a transformed phenotype and found that both caspase-2ϩ/ϩ and caspase-2Ϫ/Ϫ MEFs were unable become malignant, indicating that caspase-2 is a tumor suppressor to do so (Fig. 1C). protein. .Caspase-2؊/؊ MEFs Transform Readily with E1A and Ras Oncogenes cell survival ͉ tumorigenesis ͉ cell cycle ͉ proliferation ͉ DNA damage Given that caspase-2 deficiency leads to increased proliferation and some resistance to apoptosis induced by specific agents vasion of apoptosis is a hallmark of tumorigenesis (1). The (Fig. S1), we tested whether the loss of caspase-2 can enhance oncogenic transformation of MEFs. We used a retroviral vector Ecysteine proteases of the caspase family play a key role in the ϩ ϩ Ϫ Ϫ / / execution of apoptosis (2, 3). In tumor cells many of the defects to express E1A and Ras (17) in caspase-2 and caspase-2 in apoptosis regulation lie upstream of caspase activation rather MEFs and analyzed the properties of cells expressing these than in the caspases themselves (1, 2). Caspase-2 is one of the oncogenes. The growth rates of E1A/Ras-transformed caspase- Ϫ/Ϫ first discovered and evolutionarily most conserved of caspases 2 MEFs were significantly higher than those of transformed ϩ/ϩ (4–6). Although many in vitro studies imply an important role caspase-2 MEFs (Fig. 1B). Furthermore, E1A/Ras- ϩ/ϩ for caspase-2 in DNA damage and stress-induced cell death, transformed caspase-2 MEFs formed fewer colonies and at a caspase-2Ϫ/Ϫ mice are viable and show no overt phenotype (3, 7, slower rate compared with the rapid formation of larger colonies Ϫ/Ϫ 8). This suggests that the role of caspase-2 in cell death is by the E1A/Ras-transformed caspase-2 MEFs in soft agar redundant or is compensated by other caspases. However, there (Fig. 1 C and D; data not shown). These findings suggest that the is indirect evidence to suggest that caspase-2 may play some role loss of caspase-2 facilitates cell transformation. in cancer. For example, the human caspase-2 gene region on ؊/؊ chromosome 7q is frequently affected/deleted in leukemia (9), E1A/Ras Transformed caspase-2 Cells Are Highly Tumorigenic in Nude Mice. To evaluate the tumorigenic properties of E1A/Ras- and caspase-2 and caspase-3 levels have been proposed to be ϩ/ϩ Ϫ/Ϫ predictors of complete remission and survival in adults with transformed caspase-2 and caspase-2 MEFs, we tested acute lymphoblastic leukemia (ALL) and acute myelogenous their ability to grow in vivo in immunocompromised mice. When injected s.c. in male athymic nude mice, E1A/Ras-transformed leukemia (AML) (10, 11). Furthermore, caspase-2 levels are Ϫ/Ϫ reduced in mantle cell lymphoma and childhood ALL (12, 13). caspase-2 MEFs, from all 8 different batches of MEFs tested, Using MEFs from caspase-2Ϫ/Ϫ mice, we recently showed that produced rapid and aggressive tumors with all animals devel- oping large tumors within 10 days (all animals injected with the loss of caspase-2 results in a delayed apoptosis in response to Ϫ/Ϫ specific agents (14). We also noted that caspase-2Ϫ/Ϫ MEFs have a E1A/Ras-transformed caspase-2 MEFs were euthanized be- fore day 15 due to tumor burden; Fig. 2 A and B). During this higher rate of proliferation than their wild-type counterparts (see ϩ/ϩ below). A link between cell cycle progression and caspase-2 has period, E1A/Ras-transformed caspase-2 MEFs from multiple been identified whereby the cell cycle regulator cyclin D3 was shown to stabilize caspase-2 through possible competition with Author contributions: L.H.H. and S.K. designed research; L.H.H., R.T., L.D., and D.C. per- protease(s) that eliminate the caspase or activate it (15). Further- formed research; P.B. contributed new reagents/analytic tools; L.H.H., R.T., L.D., D.C., P.B., more, a recent study suggests that in response to ␥-radiation- and S.K. analyzed data; and L.H.H., L.D., and S.K. wrote the paper. induced DNA damage, caspase-2 induces apoptosis in a pathway The authors declare no conflict of interest. downstream of ataxia telangiectasia mutated (ATM), and ATM This article is a PNAS Direct Submission. and Rad3 related (ATR), following Chk1 inhibition (16). However, 1To whom correspondence should be addressed. E-mail: [email protected]. it is not known whether the loss of caspase-2 in vivo can potentiate This article contains supporting information online at www.pnas.org/cgi/content/full/ or facilitate tumorigenesis. In the current study we tested this 0811928106/DCSupplemental. 5336–5341 ͉ PNAS ͉ March 31, 2009 ͉ vol. 106 ͉ no. 13 www.pnas.org͞cgi͞doi͞10.1073͞pnas.0811928106 Downloaded by guest on September 29, 2021 C A 60 Casp2+/+ * Casp2 -/- ) 4 50 40 * 30 Casp2 +/+ Casp2 +/+/E1A/Ras 20 * 10 Viable cell no. (x10 no. (x10 cell Viable 0 024487296 Time (h) B 140 - - -/- Casp2+/+/E1A/Ras * Casp2 / Casp2 /E1A/Ras ) 120 Casp2 -/- 4 /E1A/Ras Casp2+/+/E1A/Ras 100 D Casp2-/-/E1A/Ras 80 300 Fig. 1. Growth properties and colony formation by * primary and E1A/Ras-transformed caspase-2ϩ/ϩ and 60 * 250 caspase-2Ϫ/Ϫ MEFs. (A) Growth data for caspase-2ϩ/ϩ Ϫ Ϫ 40 and caspase-2 / MEFs. (B) Growth of E1A/Ras- 200 transformed caspase-2ϩ/ϩ and caspase-2Ϫ/Ϫ MEFs. (C ϩ/ϩ Viable cellno. (x10 20 and D) Soft-agar colony formation by caspase-2 150 Ϫ Ϫ and caspase-2 / MEFs and E1A/Ras-transformed 0 ϩ ϩ Ϫ Ϫ 024487296 100 caspase-2 / and caspase-2 / MEFs. In panels A, B, Ϯ No. of colonies and D, results are shown as mean SEM from 3 Time (h) 50 independent experiments using MEFs isolated from 3 different embryos per genotype, and performed in 0 triplicate. *P Ͻ 0.05. batches produced small or nondetectable tumors (Fig. 2 A and 16 weeks. When we combined caspase-2 deficiency with the E␮-Myc B). The average tumor size for caspase-2Ϫ/Ϫ MEFs at day 10 was transgene, we saw an accelerated occurrence of tumors compared Ϸ3ϫ the average tumor size for caspase-2ϩ/ϩ MEFs at day 15 with E␮-Myc transgenic mice alone (Fig. 3). Interestingly, the loss ϩ ϩ Ϫ Ϫ (Fig. 2B). Although caspase-2 / and caspase-2 / MEFs were of a single caspase-2 allele was sufficient to accelerate tumor MEDICAL SCIENCES similarly transformed by the E1A/Ras retroviral vector, the delay formation. The median lifespan of 12 caspase-2ϩ/Ϫ E␮-Myc mice in the tumor formation and size of tumors produced by trans- was 12 weeks with over 90% of mice becoming terminally ill before ϩ ϩ formed caspase-2 / MEFs compared with transformed caspase- 50% of caspase-2ϩ/ϩ E␮-Myc mice were affected (Fig. 3A). Ϫ Ϫ 2 / MEFs suggest that expression of caspase-2 is required for Caspase-2Ϫ/Ϫ E␮-Myc mice had a median lifespan of 8 weeks and the inhibition of tumorigenesis.
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