Apoptosis regulation in adrenocortical carcinoma

Abstract

Apoptosis evading is a hallmark of cancer. Tumor cells are characterized by having an impaired apoptosis signaling, a fact that deregulates the balance between cell death and survival, leading to tumor development, invasion and resistance to treatment. In general, patients with adrenocortical carcinomas (ACC) have an extremely bad prognosis, which is related to disease progression and significant resistance to treatments. In this report, we performed an integrative review about the disruption of apoptosis in ACC that may underlie the characteristic poor prognosis in these patients. Although the apoptosis has been scarcely studied in ACC, the majority of the deregulation phenomena already described are anti-apoptotic. Most importantly, in a near future, targeting apoptosis modulation in ACC patients may become a promising therapeutic.

Keywords: adrenocortical carcinomas; adrenocortical tumors; apoptosis; molecular deregulations.

Figure 1

Schematic representation of apoptosis regulated by caspases. After activation of the initiator caspases, they activate executioner caspases by cleavage. Executioner caspases, when activated cleave and activate ROCK-1, PAK-2 and DFF40/45 leading to cell shrinkage, membrane blebbing and DNA fragmentation.

Figure 2

Schematic representation of extrinsic apoptotic pathway. Stimulation of death receptors of the TNF-R, Fas and DR4/5 by their respective ligands, results in receptor aggregation and recruitment of FADD and caspase-8 and caspase-10. These caspases become activated and cleaves the executioner caspases-3, caspase-6 and caspase-7, leading to apoptosis. Abnormalities in mRNA and in protein expression alterations already described in adrenocortical carcinomas are highlighted in solid and open squares, respectively.

Figure 3

Schematic representation of intrinsic apoptotic pathway. Stress signals leads to the pro-apoptotic BCL-2 family proteins activation that induce the mitochondrial outer membrane permeation (MOMP). MOMP allows the release of the Cytochrome C, AIF, EndoG, HtrA2/Omi and Smac/DIABLO. Cytochrome C release leads to the formation of apoptosome complex that triggers caspase-3, -6, -7 activation. They cleave ROCK-1, PAK-2 and DFF40/45 leading to cell shrinkage, membrane blebbing and DNA fragmentation. HtrA2/Omi and Smac/DIABLO inhibit IAPs, avoiding the caspase inhibition by them. EndoG and AIF lead to DNA fragmentation. Abnormalities in the expression of genes involved in the intrinsic apoptotic pathway in adrenocortical carcinomas are highlighted in red or green circles.