| Note | |
| | |
| Entity | Skin Cancers ( Melanoma, Basal Cell Carcinoma, Squamous Cell Carcinoma). |
| Cytogenetics | Frequent LOH in 12q22-23 locus (primary melanomas: 20-25% metastatic melanomas 35-40%). |
| Oncogenesis | The silencing of Apaf1 expression is often found in Melanomas. Two main mechanisms have been posited for APAF1 dimininution, either the allelic LOH in 12q22-23 locus and/or a transcriptional silencing by promoter methylation. The inactivation was not found in Nevi but it increased significantly in the later stages of carcinogenesis, when primary melanomas are fully developed (1-3mm of diameter). Very often such inactivation was associated with metastatic melanomas. Moreover, the APAF1 level is correlated with chemosensivity to different agents; different studies demonstrate that overexpressing or restoring a normal APAF1 level could sensitize chemoresistant melanoma cell lines, in vitro. Recently, APAF1 LOH determination on blood serum DNA has been proposed as a marker for selecting appropriate chemotherapy in stage IV melanoma patients. |
| | |
| | |
| Entity | Brain tumors (neural tumors, glial tumors) |
| Cytogenetics | Frequent LOH in 12q22-23 locus in glioblastomas (40%) |
| Oncogenesis | APAF1 seems to be downregulated or absent in Glioblastomas at mRNA and protein level. In addition, the co-overexpression of APAF1 and Caspase-9 sensitizes glioma cell lines (U-251 and U-373 MG) to p53-dependent apoptosis. Other modulations of the apoptosome-related apoptosis have been successfully conducted in order to induce apoptosis in glioma resistant lines. By contrast, APAF1 seems to be active in Neuroblastomas while there are no studies about a putative APAF1 role in other glial tumors (such as ependimoma, astrocytoma, ganglioglioma). |
| | |
| | |
| Entity | Head and neck cancers and odontogenic tumors. |
| Oncogenesis | There is no direct evidence of APAF1's role in the oncogenesis of these types of cancer even though Apaf1 loss has been correlated with gain of Cisplatin Chemoresistance in HSC-2CR cells (derived from HSC-2 head squamous carcinoma cells). |
| | |
| | |
| Entity | Gastro-intestinal tract cancers ( oesophagus cancer, gastric cancer, gallbladder cancer, ampulla of vater cancer, peritoneum cancer, vermiform appendix cancer, colon cancer, rectal cancer, cancer of the anus). |
| Oncogenesis | A low frequency of mutations (10-15 % of cases) is found in ColoRectal and Gastric Cancer. these mutations are due to the genetics of microsatellite instability and appear to be heterozygous. No evidences of APAF1 involvement have been found in the pathogenesis of the other tumors mentioned |
| | |
| | |
| Entity | Exocrinus pancreas cancers (various stages of the pancreas ductal adenocarcinoma - PDAC) |
| Cytogenetics | 12q 1ocus deletions could be considered among the most frequent deletions in PDAC. |
| Oncogenesis | There is no direct evidence of APAF1 mutations in the progression of the PDAC (some even deny its possible role completely). There are many studies, however, which point out the 12q22-23 locus LOH or mutation in PDAC. Most of the mutated genes involved (such as K-Ras, p53, p16INK4a, p19ARF) can control the APAF1 level directly or indirectly throught the action of p53 and E2F-1 which both have active binding boxes to the APAF1 promoter. |
| | |
| | |
| Entity | Liver cancer and liver metastases |
| Oncogenesis | Methylation is a common feature in regulation. While the analysis of promoters methylation in HCC samples showed that the APAF1 gene is not hypermethylated, the HepG2 cells exposed to a demethylating agent (DEM, diethyl maleate) showed an increased level of Apaf1 and of some caspases which lead to G2 phase arrest and apoptosis. |
| | |
| | |
| Entity | Lung cancer |
| Oncogenesis | There is no direct evidence for abrogation of APAF1 function in lung cancer. However, the APAF1/Caspase-9 upregulation seem to be a protective mechanism in some NSCLC ( non small cell lung carcinoma) cell lines, while in other NSCLC lines (such as the NCI-H460) an indirect APAF1 loss of function is mediated by the upregulation of XIAP (an inhibitor of Apoptosome assembly). Furthermore, a driven expression of APAF1/ Caspase-9 (through the Inibition of XIAP in NCI-H460 cells or with low dose lung cancer cell lines) seems to augment sensitivity to death. |
| | |
| | |
| Entity | Tumors of the female reproductive organs ( ovarian carcinoma, neoplasms of Fallopian tube, endometrium, cervix, vulva and vagina) |
| Oncogenesis | In ovarian carcinoma, the APAF1 gene seems to be active. However, dysfunction in the apoptosome assembly process has been correlated with chemoresistance. In contrast, loss of heterozygosity was found in the apaf1 locus in malignant ovarian germ cell tumors. There is no information about the reproductive tract. |
| | |
| | |
| Entity | Tumors of the male reproductive organs ( seminoma, nonseminomatous germ cell tumors, sex cord-stromal tumors , other testis cancers, neoplasms of prostate, tumor of the penis) |
| Cytogenetics | Frequent deletions in Chromosome 12 long and short arm in germ line tumors; LOH in 12q22-23 is present in seminomas, non-seminomatous tumors and in mixed teratomas with various reported percentage (20-45%) |
| Oncogenesis | In Germ line tumors the APAF1 locus is often deleted; however it seems that APAF1 level was normal in various analyzed lines. Interestingly, Cisplatin treatment of a embryonal carcinoma cell line, TTSC-3 lead to the differentiation of the carcinoma through the up-regulation of pro-differentiation and pro-apoptotic genes (such as APAF1, Caspase-8 and TNFR1). In Prostatic Tumor there is no evidence of APAF1 involvement; however some studies have been conducted demontrating an increase of Apaf1 at transcription level as a cellular response to chemotherapeutic agents. |
| | |
| | |
| Entity | Urinary tract tumors ( renal cell carcinoma, neoplasms of the renal pelvis, ureter, bladder, urethra) |
| Oncogenesis | The Apoptosome function seems to be active in primary samples and in a few cell lines of Renal Cell Carcinoma. There are no informations about the urinary tract. |
| | |
| | |
| Entity | Hematopoietic system tumors. |
| Oncogenesis | It's not clear if APAF1 gene is corrupted in Leukaemias and Lymphomas. However, while the methylation of the promoter was demonstrated in different kinds of leukaemia, the protein level does not correlate with the messenger level, suggesting a multistep regulation in APAF1 expression. Furthermore, it has been demonstrated that the APAF1 overexpression, conducted by in vitro transfection or by chemoadiuvants, could overcome the resistance to chemo-radiotherapeutic agents. |
| | |
| | |
| Entity | Bone and soft tissue cancers (osteoma, sarcoma, fibroma, osteosarcoma) |
| Oncogenesis | There is no direct evidence of APAF1 role in the oncogenesis of these types of cancer even though in Ewing's sarcoma cell lines the Apaf1 low level found in two different lines (STA-ET-2.1 and STA-ET-2.2) was correlated with chemoresistance to p53-dependent death stimuli compared with lines with normal APAF1 level. APAF1 was also absent and correlated with chemoresistance in the HT-1080 fibrosacroma cell line. |
| | |
| | |
| Entity | Various tumors ( eye tumor, heart and great vessels tumors, neoplasm of the endocrine glands and of the diffuse endocrine system, tumor of mesotheliums) |
| Oncogenesis | At present, there is no direct evidence of APAF1 involvement in the carcinogenesis of these neoplasms. |
| | |
| Apoptosomes: engines for caspase activation. |
| Adams JM, Cory S |
| Current opinion in cell biology. 2002 ; 14 (6) : 715-720. |
| PMID 12473344 |
| |
| Proteasome inhibitor-induced apoptosis of B-chronic lymphocytic leukaemia cells involves cytochrome c release and caspase activation, accompanied by formation of an approximately 700 kDa Apaf-1 containing apoptosome complex. |
| Almond JB, Snowden RT, Hunter A, Dinsdale D, Cain K, Cohen GM |
| Leukemia : official journal of the Leukemia Society of America, Leukemia Research Fund, U.K. 2001 ; 15 (9) : 1388-1397. |
| PMID 11516099 |
| |
| Analysis of APAF-1 expression in human cutaneous melanoma progression. |
| Baldi A, Santini D, Russo P, Catricalà C, Amantea A, Picardo M, Tatangelo F, Botti G, Dragonetti E, Murace R, Tonini G, Natali PG, Baldi F, Paggi MG |
| Experimental dermatology. 2004 ; 13 (2) : 93-97. |
| PMID 15009102 |
| |
| Expression and functional analysis of Apaf-1 isoforms. Extra Wd-40 repeat is required for cytochrome c binding and regulated activation of procaspase-9. |
| Benedict MA, Hu Y, Inohara N, Nez G |
| The Journal of biological chemistry. 2000 ; 275 (12) : 8461-8468. |
| PMID 10722681 |
| |
| Hairy-cell leukaemia as a model for drug development. |
| Carson DA, Leoni LM |
| Best practice & research. Clinical haematology. 2003 ; 16 (1) : 83-89. |
| PMID 12670467 |
| |
| Transcriptional and physiological responses of HepG2 cells exposed to diethyl maleate: time course analysis. |
| Casey W, Anderson S, Fox T, Dold K, Colton H, Morgan K |
| Physiological genomics. 2002 ; 8 (2) : 115-122. |
| PMID 11875189 |
| |
| Apaf1 and the apoptotic machinery. |
| Cecconi F |
| Cell death and differentiation. 1999 ; 6 (11) : 1087-1098. |
| PMID 10578178 |
| |
| Apaf1 in developmental apoptosis and cancer: how many ways to die? |
| Cecconi F, Gruss P |
| Cellular and molecular life sciences : CMLS. 2001 ; 58 (11) : 1688-1697. |
| PMID 11706994 |
| |
| Apoptosis: molecular regulation of cell death and hematologic malignancies. |
| Chiarugi V, Cinelli M, Magnelli L, Dello SP |
| Molecular biotechnology. 2002 ; 20 (3) : 305-314. |
| PMID 11936259 |
| |
| Reduced Apaf-1 expression in human cutaneous melanomas. |
| Dai DL, Martinka M, Bush JA, Li G |
| British journal of cancer. 2004 ; 91 (6) : 1089-1095. |
| PMID 15305193 |
| |
| Molecular targeting of drug delivery systems to ovarian cancer by BH3 and LHRH peptides. |
| Dharap SS, Qiu B, Williams GC, Sinko P, Stein S, Minko T |
| Journal of controlled release : official journal of the Controlled Release Society. 2003 ; 91 (1-2) : 61-73. |
| PMID 12932638 |
| |
| Cancer as an epigenetic disease: DNA methylation and chromatin alterations in human tumours. |
| Esteller M, Herman JG |
| The Journal of pathology. 2002 ; 196 (1) : 1-7. |
| PMID 11748635 |
| |
| Modulation of pro- and anti-apoptotic factors in human melanoma cells exposed to histone deacetylase inhibitors. |
| Facchetti F, Previdi S, Ballarini M, Minucci S, Perego P, La Porta CA |
| Apoptosis : an international journal on programmed cell death. 2004 ; 9 (5) : 573-582. |
| PMID 15314285 |
| |
| Physiological and pathological roles of Apaf1 and the apoptosome. |
| Ferraro E, Corvaro M, Cecconi F |
| Journal of cellular and molecular medicine. 2003 ; 7 (1) : 21-34. |
| PMID 12767258 |
| |
| Role of DNA methylation in the suppression of Apaf-1 protein in human leukaemia. |
| Fu WN, Bertoni F, Kelsey SM, McElwaine SM, Cotter FE, Newland AC, Jia L |
| Oncogene. 2003 ; 22 (3) : 451-455. |
| PMID 12545166 |
| |
| Apaf-1XL is an inactive isoform compared with Apaf-1L. |
| Fu WN, Kelsey SM, Newland AC, Jia L |
| Biochemical and biophysical research communications. 2001 ; 282 (1) : 268-272. |
| PMID 11264002 |
| |
| Allelic imbalance of 12q22-23 associated with APAF-1 locus correlates with poor disease outcome in cutaneous melanoma. |
| Fujimoto A, Takeuchi H, Taback B, Hsueh EC, Elashoff D, Morton DL, Hoon DS |
| Cancer research. 2004 ; 64 (6) : 2245-2250. |
| PMID 15026369 |
| |
| Apaf-1 is a mediator of E2F-1-induced apoptosis. |
| Furukawa Y, Nishimura N, Furukawa Y, Satoh M, Endo H, Iwase S, Yamada H, Matsuda M, Kano Y, Nakamura M |
| The Journal of biological chemistry. 2002 ; 277 (42) : 39760-39768. |
| PMID 12149244 |
| |
| 5-aza-2'-deoxycytidine upregulates caspase-9 expression cooperating with p53-induced apoptosis in human lung cancer cells. |
| Gomyo Y, Sasaki J, Branch C, Roth JA, Mukhopadhyay T |
| Oncogene. 2004 ; 23 (40) : 6779-6787. |
| PMID 15273730 |
| |
| Autocrine motility factor signaling induces tumor apoptotic resistance by regulations Apaf-1 and Caspase-9 apoptosome expression. |
| Haga A, Funasaka T, Niinaka Y, Raz A, Nagase H |
| International journal of cancer. Journal international du cancer. 2003 ; 107 (5) : 707-714. |
| PMID 14566819 |
| |
| Frameshift mutations at mononucleotide repeats in RAD50 recombinational DNA repair gene in colorectal cancers with microsatellite instability. |
| Ikenoue T, Togo G, Nagai K, Ijichi H, Kato J, Yamaji Y, Okamoto M, Kato N, Kawabe T, Tanaka A, Matsumura M, Shiratori Y, Omata M |
| Japanese journal of cancer research : Gann. 2001 ; 92 (6) : 587-591. |
| PMID 11429044 |
| |
| Resveratrol modifies the expression of apoptotic regulatory proteins and sensitizes non-Hodgkin's lymphoma and multiple myeloma cell lines to paclitaxel-induced apoptosis. |
| Jazirehi AR, Bonavida B |
| Molecular cancer therapeutics. 2004 ; 3 (1) : 71-84. |
| PMID 14749477 |
| |
| Role of Smac in human leukaemic cell apoptosis and proliferation. |
| Jia L, Patwari Y, Kelsey SM, Srinivasula SM, Agrawal SG, Alnemri ES, Newland AC |
| Oncogene. 2003 ; 22 (11) : 1589-1599. |
| PMID 12642862 |
| |
| Apaf-1 protein deficiency confers resistance to cytochrome c-dependent apoptosis in human leukemic cells. |
| Jia L, Srinivasula SM, Liu FT, Newland AC, Fernandes-Alnemri T, Alnemri ES, Kelsey SM |
| Blood. 2001 ; 98 (2) : 414-421. |
| PMID 11435311 |
| |
| Response of Ewing tumor cells to forced and activated p53 expression. |
| Kovar H, Pospisilova S, Jug G, Printz D, Gadner H |
| Oncogene. 2003 ; 22 (21) : 3193-3204. |
| PMID 12761489 |
| |
| Increased expression of Apaf-1 and procaspase-3 and the functionality of intrinsic apoptosis apparatus in non-small cell lung carcinoma. |
| Krepela E, Proch´zka J, Liul X, Fiala P, Kinkor Z |
| Biological chemistry. 2004 ; 385 (2) : 153-168. |
| PMID 15101558 |
| |
| Inhibition of caspase-9 activity and Apaf-1 expression in cisplatin-resistant head and neck squamous cell carcinoma cells. |
| Kuwahara D, Tsutsumi K, Oyake D, Ohta T, Nishikawa H, Koizuka I |
| Auris, nasus, larynx. 2003 ; 30 Suppl : S85-S88. |
| PMID 12543167 |
| |
| Dysfunctional apoptosome activation in ovarian cancer: implications for chemoresistance. |
| Liu JR, Opipari AW, Tan L, Jiang Y, Zhang Y, Tang H, Nuñez G |
| Cancer research. 2002 ; 62 (3) : 924-931. |
| PMID 11830553 |
| |
| Tumor suppressor genes. |
| Macleod K |
| Current opinion in genetics & development. 2000 ; 10 (1) : 81-93. |
| PMID 10679386 |
| |
| Preliminary evaluation of caspases-dependent apoptosis signaling pathways of free and HPMA copolymer-bound doxorubicin in human ovarian carcinoma cells. |
| Minko T, Kopeckov´ P, Kopecek J |
| Journal of controlled release : official journal of the Controlled Release Society. 2001 ; 71 (3) : 227-237. |
| PMID 11295216 |
| |
| Enhancing the anticancer efficacy of camptothecin using biotinylated poly(ethylene glycol) conjugates in sensitive and multidrug-resistant human ovarian carcinoma cells. |
| Minko T, Paranjpe PV, Qiu B, Lalloo A, Won R, Stein S, Sinko PJ |
| Cancer chemotherapy and pharmacology. 2002 ; 50 (2) : 143-150. |
| PMID 12172980 |
| |
| Differential expression of genes induced by resveratrol in LNCaP cells: P53-mediated molecular targets. |
| Narayanan BA, Narayanan NK, Re GG, Nixon DW |
| International journal of cancer. Journal international du cancer. 2003 ; 104 (2) : 204-212. |
| PMID 12569576 |
| |
| APAF-1-ALT, a novel alternative splicing form of APAF-1, potentially causes impeded ability of undergoing DNA damage-induced apoptosis in the LNCaP human prostate cancer cell line. |
| Ogawa T, Shiga K, Hashimoto S, Kobayashi T, Horii A, Furukawa T |
| Biochemical and biophysical research communications. 2003 ; 306 (2) : 537-543. |
| PMID 12804598 |
| |
| Overexpression of Apaf-1 promotes apoptosis of untreated and paclitaxel- or etoposide-treated HL-60 cells. |
| Perkins C, Kim CN, Fang G, Bhalla KN |
| Cancer research. 1998 ; 58 (20) : 4561-4566. |
| PMID 9788601 |
| |
| The role of Apaf-1, caspase-9, and bid proteins in etoposide- or paclitaxel-induced mitochondrial events during apoptosis. |
| Perkins CL, Fang G, Kim CN, Bhalla KN |
| Cancer research. 2000 ; 60 (6) : 1645-1653. |
| PMID 10749135 |
| |
| Apoptosis defects and chemotherapy resistance: molecular interaction maps and networks. |
| Pommier Y, Sordet O, Antony S, Hayward RL, Kohn KW |
| Oncogene. 2004 ; 23 (16) : 2934-2949. |
| PMID 15077155 |
| |
| Regulation of apoptosis by p53 in UV-irradiated human epidermis, psoriatic plaques and senescent keratinocytes. |
| Qin JZ, Chaturvedi V, Denning MF, Bacon P, Panella J, Choubey D, Nickoloff BJ |
| Oncogene. 2002 ; 21 (19) : 2991-3002. |
| PMID 12082529 |
| |
| Promoter hypermethylation of cancer-related genes: a strong independent prognostic factor in acute lymphoblastic leukemia. |
| Roman-Gomez J, Jimenez-Velasco A, Castillejo JA, Agirre X, Barrios M, Navarro G, Molina FJ, Calasanz MJ, Prosper F, Heiniger A, Torres A |
| Blood. 2004 ; 104 (8) : 2492-2498. |
| PMID 15198948 |
| |
| Fas-mediated apoptosome formation is dependent on reactive oxygen species derived from mitochondrial permeability transition in Jurkat cells. |
| Sato T, Machida T, Takahashi S, Iyama S, Sato Y, Kuribayashi K, Takada K, Oku T, Kawano Y, Okamoto T, Takimoto R, Matsunaga T, Takayama T, Takahashi M, Kato J, Niitsu Y |
| Journal of immunology (Baltimore, Md. : 1950). 2004 ; 173 (1) : 285-296. |
| PMID 15210786 |
| |
| Co-transduction of Apaf-1 and caspase-9 highly enhances p53-mediated apoptosis in gliomas. |
| Shinoura N, Sakurai S, Shibasaki F, Asai A, Kirino T, Hamada H |
| British journal of cancer. 2002 ; 86 (4) : 587-595. |
| PMID 11870542 |
| |
| Apoptosis and melanoma chemoresistance. |
| Soengas MS, Lowe SW |
| Oncogene. 2003 ; 22 (20) : 3138-3151. |
| PMID 12789290 |
| |
| Mechanisms of paclitaxel-induced apoptosis in an ovarian cancer cell line and its paclitaxel-resistant clone. |
| Sugimura M, Sagae S, Ishioka S, Nishioka Y, Tsukada K, Kudo R |
| Oncology. 2004 ; 66 (1) : 53-61. |
| PMID 15031599 |
| |
| Evaluation of Apaf-1 and procaspases-2, -3, -7, -8, and -9 as potential prognostic markers in acute leukemia. |
| Svingen PA, Karp JE, Krajewski S, Mesner PW Jr, Gore SD, Burke PJ, Reed JC, Lazebnik YA, Kaufmann SH |
| Blood. 2000 ; 96 (12) : 3922-3931. |
| PMID 11090079 |
| |
| Caspase-9 and Apaf-1 are expressed and functionally active in human neuroblastoma tumor cell lines with 1p36 LOH and amplified MYCN. |
| Teitz T, Wei T, Liu D, Valentine V, Valentine M, Grenet J, Lahti JM, Kidd VJ |
| Oncogene. 2002 ; 21 (12) : 1848-1858. |
| PMID 11896617 |
| |
| Frequent LOH at chromosome 12q22-23 and Apaf-1 inactivation in glioblastoma. |
| Umetani N, Hoon DS |
| Brain pathology (Zurich, Switzerland). 2004 ; 14 (2) : page 224; author reply 224. |
| PMID 15193036 |
| |
| A comparison of the expression and properties of Apaf-1 and Apaf-1L. |
| Walke DW, Morgan JI |
| Brain research. 2000 ; 886 (1-2) : 73-81. |
| PMID 11119689 |
| |
| Frequent LOH at chromosome 12q22-23 and Apaf-1 inactivation in glioblastoma. |
| Watanabe T, Hirota Y, Arakawa Y, Fujisawa H, Tachibana O, Hasegawa M, Yamashita J, Hayashi Y |
| Brain pathology (Zurich, Switzerland). 2003 ; 13 (4) : 431-439. |
| PMID 14655749 |
| |
| Defective cytochrome c-dependent caspase activation in ovarian cancer cell lines due to diminished or absent apoptotic protease activating factor-1 activity. |
| Wolf BB, Schuler M, Li W, Eggers-Sedlet B, Lee W, Tailor P, Fitzgerald P, Mills GB, Green DR |
| The Journal of biological chemistry. 2001 ; 276 (36) : 34244-34251. |
| PMID 11429402 |
| |
| Frameshift mutations in Fas, Apaf-1, and Bcl-10 in gastro-intestinal cancer of the microsatellite mutator phenotype. |
| Yamamoto H, Gil J, Schwartz S Jr, Perucho M |
| Cell death and differentiation. 2000 ; 7 (2) : 238-239. |
| PMID 10819600 |
| |
| Predominant suppression of apoptosome by inhibitor of apoptosis protein in non-small cell lung cancer H460 cells: therapeutic effect of a novel polyarginine-conjugated Smac peptide. |
| Yang L, Mashima T, Sato S, Mochizuki M, Sakamoto H, Yamori T, Oh-Hara T, Tsuruo T |
| Cancer research. 2003 ; 63 (4) : 831-837. |
| PMID 12591734 |
| |
| Methylation profiling of twenty promoter-CpG islands of genes which may contribute to hepatocellular carcinogenesis. |
| Yu J, Ni M, Xu J, Zhang H, Gao B, Gu J, Chen J, Zhang L, Wu M, Zhen S, Zhu J |
| BMC cancer. 2002 ; 2 : page 29. |
| PMID 12433278 |
| |
