2D-DIGE proteomic analysis identifies new potential therapeutic targets for adrenocortical carcinoma

Abstract

Adrenocortical carcinoma (ACC) is a rare aggressive tumor with poor prognosis when metastatic at diagnosis. The tumor biology is still mostly unclear, justifying the limited specificity and efficacy of the anti-cancer drugs currently available. This study reports the first proteomic analysis of ACC by using two-dimensional-differential-in-gel-electrophoresis (2D-DIGE) to evaluate a differential protein expression profile between adrenocortical carcinoma and normal adrenal. Mass spectrometry, associated with 2D-DIGE analysis of carcinomas and normal adrenals, identified 22 proteins in 27 differentially expressed 2D spots, mostly overexpressed in ACC. Gene ontology analysis revealed that most of the proteins concurs towards a metabolic shift, called the Warburg effect, in adrenocortical cancer. The differential expression was validated by Western blot for Aldehyde-dehydrogenase-6-A1,Transferrin, Fascin-1,Lamin A/C,Adenylate-cyclase-associated-protein-1 and Ferredoxin-reductase. Moreover, immunohistochemistry performed on paraffin-embedded ACC and normal adrenal specimens confirmed marked positive staining for all 6 proteins diffusely expressed by neoplastic cells, compared with normal adrenal cortex.In conclusion, our preliminary findings reveal a different proteomic profile in adrenocortical carcinoma compared with normal adrenal cortex characterized by overexpression of mainly metabolic enzymes, thus suggesting the Warburg effect also occurs in ACC. These proteins may represent promising novel ACC biomarkers and potential therapeutic targets if validated in larger cohorts of patients.

Metformin as a new anti-cancer drug in adrenocortical carcinoma

“…The high rate of anabolic processes sustaining cancer cell proliferation and progression in a ROS-rich environment requires a high chaperone activity to ensure a correct protein folding process. Increased HSPs expression has been observed in various types of malignancies [46], including adrenocortical cancer [47]. In particular, HSP27, 60 and 70 play a pivotal role in dampening the apoptotic processes at mitochondrial level [45, 48], thus representing promising anti-tumor targets for the development of anti-cancer drugs.…”

The next step: mechanisms driving adrenocortical carcinoma metastasis

“…These findings further suggest (see the study by Pinheiro et al mentioned earlier) that a metabolic shift toward aerobic glycolysis (Warburg effect) takes place in malignant ACT. More recently, another study confirmed that ACCs harbor significant changes in their glucose metabolic pathways and in addition identified fascin-1 as overexpressed in ACC compared to normal adrenal (Poli et al 2015). This protein has an important role in cytoskeletal organization and is associated with malignancy in a variety of cancers (Hashimoto et al 2011).…”

The challenge of developmental therapeutics for adrenocortical carcinoma

“…Poli et al reported a different proteomic profile in adrenocortical carcinoma compared with normal adrenal cortex characterized by overexpression of mainly metabolic enzymes that can be a potential target for novel therapeutics. [146]…”