title: Absence of caspase 3 activation in neoplastic cells of nasopharyngeal carcinoma biopsies predicts rapid fatal outcome.
abstract: Poor prognosis in nasopharyngeal carcinoma patients may result from resistance to the apoptosis-inducing effect of radio- and/or chemotherapy. Apoptosis depends on proper activation of caspase 3, resulting in cleavage of key proteins like PARP-1. To investigate whether disruption of the apoptosis pathway results in therapy-resistant tumour cells, we investigated whether absence of caspase 3 activation in tumour biopsies of nasopharyngeal carcinoma patients is related to poor clinical outcome. Moreover, we investigated whether absence of caspase 3 activation is related to loss of procaspase 3 expression or expression of the apoptosis regulators p53, bcl-2 and XIAP. We studied 36 Indonesian nasopharyngeal carcinoma patients without evidence of distant metastases who were treated with curative intent by radiotherapy only. Activation of caspase 3 and expression of the different markers were determined using specific antibodies. Levels of caspase 3 activation were determined by quantifying positively staining tumour cells. Nasopharyngeal carcinoma-derived C15 and C17 tumour cells were used as control. Absence of caspase 3 activation was strongly related to a poor clinical response to radiotherapy and to a higher T and N stage, resulting in a particularly poor clinical outcome with regard to progression-free (P<0.0001) and overall survival time (P<0.0001). Absence of caspase 3 activation was significantly correlated to loss of expression of procaspase 3 (P=0.04). In nasopharyngeal carcinoma patients treated with curative intent, absence of active caspase 3-positive neoplastic cells predicts rapid fatal outcome, and is associated with poor response to radiotherapy and high T and N stage at time of presentation.
authors.affiliation: Department of Pathology, VU Medical Center, Amsterdam, The Netherlands. jj.oudejans@azvu.nl
authors.forename: Joost J
authors.initials: JJ
authors.lastname: Oudejans
authors.forename: Ahemd
authors.initials: A
authors.lastname: Harijadi
authors.forename: Saskia A G M
authors.initials: SA
authors.lastname: Cillessen
authors.forename: Pierre
authors.initials: P
authors.lastname: Busson
authors.forename: I Bing
authors.initials: IB
authors.lastname: Tan
authors.forename: Danny F
authors.initials: DF
authors.lastname: Dukers
authors.forename: Wim
authors.initials: W
authors.lastname: Vos
authors.forename: Bambang
authors.initials: B
authors.lastname: Hariwiyanto
authors.forename: Jaap
authors.initials: J
authors.lastname: Middeldorp
authors.forename: Chris J L M
authors.initials: CJ
authors.lastname: Meijer
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D001706:Biopsy; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism*; D045744:Cell Line, Tumor; D004789:Enzyme Activation; D005047:Etoposide / Q000494:pharmacology; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D016246:Lymphocytes, Tumor-Infiltrating / Q000473:pathology; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009303:Nasopharyngeal Neoplasms / Q000201:enzymology / Q000401:mortality / Q000473:pathology*; D009305:Nasopharynx / Q000737:chemistry / Q000473:pathology; D011506:Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D016019:Survival Analysis; D015996:Survival Rate; D013602:T-Lymphocytes, Cytotoxic / Q000473:pathology; D051636:X-Linked Inhibitor of Apoptosis Protein
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D011506:Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; D005047:Etoposide; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases