Peripheral Benzodiazepine Receptor Antisense Knockout Increases Tumorigenicity of MA-10 Leydig Cells in Vivo and in Vitro

Abstract

Peripheral benzodiazepine receptors (PBR), first described more than 20 years ago, have been attributed with many putative functions including ones in cellular proliferation and cellular respiration. Hence, it is quite conceivable that deregulation of this receptor could lead to pathology. We and others have reported the existence of PBR overexpression in different human and nonhuman malignancies, but it has never been made clear whether this aberrant malignant PBR expression is a cause or consequence of the cancer. In the current study we induced PBR underexpression by downregulating one critical subunit of the PBR complex, the isoquinoline-binding protein (IBP), using the stable antisense knockout approach, in the MA-10 Leydig cell line. Resultant clones, showing PBR deregulation, also demonstrated increased tumorigenicity, using both in vitro (loss of contact inhibition and growth in soft agar) and in vivo (increased mortality on grafting back into isogenic mice) assays. We suggest that this type of deregulation could be a later event in natural tumor progression. Consequently, PBR deregulation should be more closely studied in human malignancy.

The permeability transition pore complex in cancer cell death

“…However, although these data indicate a clear correlation of progressive tumorigenesis with the upregulation of PBR, the in vivo situation seems to be more complicated. In skin cancer, for example, PBR is downregulated (Morgan et al, 2004) and a reduction of PBR by antisense increased -not decreasedtumorigenicity in two studies (Weisinger et al, 2004;Levin et al, 2005). Consequently, one must keep in mind that the data above establish a correlation between the expression level of PBR and progressive tumorigenesis and not necessarily a causative relation.…”

Translocator Protein-Mediated Stabilization of Mitochondrial Architecture during Inflammation Stress in Colonic Cells

“…Indeed, the intracellular signaling involved in the inflammation process must be different between the brain and intestine, as well as in the existing complexes. Moreover, the opposite effect of TSPO expression on cell viability might originate from the use of different experimental conditions to delete TSPO, such as antisense RNAs [ 48 , 60 ].…”

PK11195 potently sensitizes to apoptosis induction independently from the peripheral benzodiazepin receptor

“…The PBR protein is overexpressed in some tumors, and this overexpression has a negative prognostic impact on breast cancer and colorectal cancer (Maaser et al, 2005). In contrast, knockdown of PBR expression by an antisense construct enhances the tumorigenicity of murine cancer cell lines (Weisinger et al, 2004). Ligation of PBR with synthetic ligands such as 1-(2-chlorophenyl-N-methylpropyl)-3-isoquinolinecarboxamide (PK11195) or 7-chloro-5-(4-chlorophenyl)-1,3-dihydro-1-methyl-2H-1,4-benzodiazepin-2-one (Ro5-4864) facilitates apoptosis induction in human tumor cells by a variety of chemotherapeutic agents, including doxorubicin (Hirsch et al, 1998;Sutter et al, 2004), daunorubicin (Jakubikova et al, 2002), etoposide (Decaudin et al, 2002;Okaro et al, 2002), 5-fluorouracil, UV and g-irradiation (Okaro et al, 2002), ifosfamide (Decaudin et al, 2002), paclitaxel, docetaxel (Hirsch et al, 1998;Sutter et al, 2004), colchicine (Jorda et al, 2005), arsenicals (Larochette et al, 1999;Muscarella et al, 2003), lonidamine (Ravagnan et al, 1999), and bortezomib (Chauhan et al, 2004).…”