pp32/PHAPI determines the apoptosis response of non-small-cell lung cancer

Abstract

During malignant transformation, cancer cells have to evade cell-intrinsic tumor suppressor mechanisms including apoptosis, thus acquiring a phenotype that is relatively resistant to clinically applied anticancer therapies. Molecular characterization of apoptotic signal transduction defects may help to identify prognostic markers and to develop novel therapeutic strategies. To this end we have undertaken functional analyses of drug-induced apoptosis in human non-small cell-lung cancer (NSCLC) cells. We found that primary drug resistance correlated with defects in apoptosome-dependent caspase activation in vitro. While cytochrome c-induced apoptosome formation was maintained, the subsequent activation of caspase-9 and -3 was abolished in resistant NSCLC. The addition of recombinant pp32/putative human HLA class II-associated protein (pp32/PHAPI), described as a putative tumor suppressor in prostate cancer, successfully restored defective cytochrome c-induced caspase activation in vitro. Conditional expression of pp32/PHAPI sensitized NSCLC cells to apoptosis in vitro and in a murine tumor model in vivo. Immunohistochemical analyses of tumor samples from NSCLC patients revealed that the expression of pp32/PHAPI correlated with an improved outcome following chemotherapy. These results identify pp32/PHAPI as regulator of the apoptosis response of cancer cells in vitro and in vivo, and as a predictor of survival following chemotherapy for advanced NSCLC.

Down-regulated expression of apoptosis-associated genes APIP and UACA in non-small cell lung carcinoma

“…The activation of apoptosome apparatus is often impaired in non-small cell lung carcinoma (NSCLC) cells and tissues (21,22). The molecular basis of apoptosome apparatus suppression in NSCLC is still unknown and there is evidence that it does not involve the segregatory binding of procaspase-9 to TUCAN (23) or direct inhibition of caspase-9 by XIAP (22,24).…”

“…There is evidence that the hypersensitivity of certain malignant neoplasms such as brain tumours and breast carcinomas, as opposed to their normal tissue counterparts, to the cyt-c-induced apoptosis is due to up-regulation of Apaf-1 and its regulator PHAPI, respectively, in cancer cells (11,12). On the other hand, deficient signalling in the apoptosome pathway, due to the lack of apoptosome core component expression or apoptosome dysfunction, contributes to tumourigenesis and progression of malignant neoplasms as well as to their chemo-and radioresistance (8,(13)(14)(15)(16)(17)(18)(19)(20).The activation of apoptosome apparatus is often impaired in non-small cell lung carcinoma (NSCLC) cells and tissues (21,22). The molecular basis of apoptosome apparatus suppression in NSCLC is still unknown and there is evidence that it does not involve the segregatory binding of procaspase-9 to TUCAN (23) or direct inhibition of caspase-9 by XIAP (22,24).…”

Low-Dose Methotrexate Inhibits Methionine S-Adenosyltransferase In Vitro and In Vivo

“…Numerous genes are altered significantly by ectopic expression of HoxD10 with cDNA microarray analysis. These candidate targets have been reported to participate in cellular growth, apoptosis, adhesion and angiogenesis (34)(35)(36)(37)(38)(39)(40)(41). We further validated that HCLS1, ANP32A, PDGFRL, IGFBP3 and CXCL9 were upregulated, while RAC2, NTS, KRT5 and TUSC3 downregulated by qPCR analysis.…”

“…Furthermore, two other HoxD10 downstream targets, ANP32A and HCLS1, also were involved in cell apoptosis. ANP32A is an important cofactor of caspase activation, which may enhance the activity of caspase 3 and determine sensitivity to apoptosis (36)(37)(38). HCLS1 is reported to increase apoptosis by activation of caspase 3 activity (39).…”

Acidic nuclear phosphoprotein 32kDa (ANP32)B-deficient mouse reveals a hierarchy of ANP32 importance in mammalian development

“…The ANP32 proteins have been implicated in a broad array of physiological processes, including cell differentiation (4-7), apoptotic cell death (8)(9)(10)(11)(12)(13)(14), and cell proliferation (15)(16)(17). Diverse mechanisms have been postulated for how these proteins perform their function(s).…”