The potential anticancer agent PK11195 induces apoptosis irrespective of p53 and ATM status in chronic lymphocytic leukemia cells

Santidrián, Antonio F.; Cosialls, Ana M.; Coll-Mulet, Llorenç; Iglesias-Serret, Daniel; Frías, Mercè de; González-Gironès, Diana M.; Campàs, Clara; Domingo, Alícia; Pons, Gabriel; Gil, Joan

doi:10.3324/haematol.11194

Cited by 27 publications

(26 citation statements)

References 52 publications

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“…It is a suggested component of the mitochondrial permeability transition pore (mPTP) 9 although supporting evidence for this is still missing. 10 A role for TSPO in the execution of apoptosis has long been proposed and its natural and synthetic ligands i) endozepine, 11,12 ii) PK11195 [13][14][15][16] and iii) Ro-54864 17 are widely exploited as chemotherapy co-adjuvants. Other functions linked to TSPO include: i) the regulation of mitochondrial ATP production, 18,19 ii) the generation of reactive oxygen species, 20,21 and iii) the modulation of Ca 2C signaling.…”

Section: Introductionmentioning

confidence: 99%

TSPO interacts with VDAC1 and triggers a ROS-mediated inhibition of mitochondrial quality control

et al. 2014

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The 18-kDa TSPO (translocator protein) localizes on the outer mitochondrial membrane (OMM) and participates in cholesterol transport. Here, we report that TSPO inhibits mitochondrial autophagy downstream of the PINK1-PARK2 pathway, preventing essential ubiquitination of proteins. TSPO abolishes mitochondrial relocation of SQSTM1/p62 (sequestosome 1), and consequently that of the autophagic marker LC3 (microtubule-associated protein 1 light chain 3), thus leading to an accumulation of dysfunctional mitochondria, altering the appearance of the network. Independent of cholesterol regulation, the modulation of mitophagy by TSPO is instead dependent on VDAC1 (voltagedependent anion channel 1), to which TSPO binds, reducing mitochondrial coupling and promoting an overproduction of reactive oxygen species (ROS) that counteracts PARK2-mediated ubiquitination of proteins. These data identify TSPO as a novel element in the regulation of mitochondrial quality control by autophagy, and demonstrate the importance for cell homeostasis of its expression ratio with VDAC1.

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Section: Introductionmentioning

confidence: 99%

TSPO interacts with VDAC1 and triggers a ROS-mediated inhibition of mitochondrial quality control

et al. 2014

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“…These genes include several genes, like FAM24B, ZNF75A, ZNF274, ZNF667, FLJ10769, and FAT, for which little is known about their functions, but also some genes that are interesting because of their potential role in ALL. Silencing of DNAJC15 by methylation has been associated with increased chemotherapeutic resistance in ovarian cancer (Shridhar et al 2001) and TSPO is the ligand for several anticancer agents (Santidrian et al 2007) and has been shown to be overexpressed in chronic lymphocytic leukemia (CLL) cells (Carayon et al 1996).…”

Section: Discussionmentioning

confidence: 99%

Allele-specific gene expression patterns in primary leukemic cells reveal regulation of gene expression by CpG site methylation

Milani

Lundmark²,

Nordlund³

et al. 2008

Genome Res.

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To identify genes that are regulated by cis-acting functional elements in acute lymphoblastic leukemia (ALL) we determined the allele-specific expression (ASE) levels of 2529 genes by genotyping a genome-wide panel of single nucleotide polymorphisms in RNA and DNA from bone marrow and blood samples of 197 children with ALL. Using a reproducible, quantitative genotyping method and stringent criteria for scoring ASE, we found that 16% of the analyzed genes display ASE in multiple ALL cell samples. For most of the genes, the level of ASE varied largely between the samples, from 1.4-fold overexpression of one allele to apparent monoallelic expression. For genes exhibiting ASE, 55% displayed bidirectional ASE in which overexpression of either of the two SNP alleles occurred. For bidirectional ASE we also observed overall higher levels of ASE and correlation with the methylation level of these sites. Our results demonstrate that CpG site methylation is one of the factors that regulates gene expression in ALL cells.

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“…17 Samples from patients 7 and 28 have 11q22 deletion and do not express ATM protein. 17,18 Patient 7 has the 11q23 deletion in one allele in 86% of peripheral blood lymphocytes, and patient 29 has the 11q23 deletion determined by genomic multiplex ligation-dependent probe amplification (MLPA; relative copy number value ϭ 0.57). 17 …”

Section: Cll Samples and Cell Isolationmentioning

confidence: 99%

AICAR induces apoptosis independently of AMPK and p53 through up-regulation of the BH3-only proteins BIM and NOXA in chronic lymphocytic leukemia cells

Santidrián

González-Gironès

Iglesias-Serret

et al. 2010

Blood

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The potential anticancer agent PK11195 induces apoptosis irrespective of p53 and ATM status in chronic lymphocytic leukemia cells

Cited by 27 publications

References 52 publications

TSPO interacts with VDAC1 and triggers a ROS-mediated inhibition of mitochondrial quality control

TSPO interacts with VDAC1 and triggers a ROS-mediated inhibition of mitochondrial quality control

Allele-specific gene expression patterns in primary leukemic cells reveal regulation of gene expression by CpG site methylation

AICAR induces apoptosis independently of AMPK and p53 through up-regulation of the BH3-only proteins BIM and NOXA in chronic lymphocytic leukemia cells

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