Modulation of Autophagy in Adrenal Tumors

Abstract

Adrenal masses are one of the most common tumors in humans. The majority are benign and non-functioning and therefore do not require immediate treatment. In contrast, the rare adrenal malignant tumors are often highly aggressive and with poor prognosis. Besides usually being detected in advanced stages, often already with metastases, one of the reasons of the unfavorable outcome of the patients with adrenal cancer is the absence of effective treatments. Autophagy is one of the intracellular pathways targeted by several classes of chemotherapeutics. Mitotane, the most commonly used drug for the treatment of adrenocortical carcinoma, was recently shown to also modulate autophagy. Autophagy is a continuous programmed cellular process which culminates with the degradation of cellular organelles and proteins. However, being a dynamic mechanism, understanding the autophagic flux can be highly complex. The role of autophagy in cancer has been described paradoxically: initially described as a tumor pro-survival mechanism, different studies have been showing that it may result in other outcomes, namely in tumor cell death. In adrenal tumors, this dual role of autophagy has also been addressed in recent years. Studies reported both induction and inhibition of autophagy as a treatment strategy of adrenal malignancies. Importantly, most of these studies were performed using cell lines. Consequently clinical studies are still required. In this review, we describe what is known about the role of autophagy modulation in treatment of adrenal tumors. We will also highlight the aspects that need further evaluation to understand the paradoxical role of autophagy in adrenal tumors.

Preclinical Evidence of Progesterone as a New Pharmacological Strategy in Human Adrenocortical Carcinoma Cell Lines

“…The mechanism underlying the cytotoxic effect of Pg on TVBF-7 was seemingly linked to an increase in LC3-II levels, representing the activation of autophagy. The role of autophagy in the ACC context is challenging because it plays a double-edged role not only as a survival response to chemotherapeutic drugs, resulting in treatment failure, but also as an important mechanism underlying tumor cell suicide [ 35 , 36 , 37 ]. The cytoprotective function of autophagy is activated in many circumstances by suppressing apoptosis, and this evidence justifies the observation of an increase in the cell viability in TVBF-7 cells exposed to Pg.…”

Preclinical evidence of progesterone as a new pharmacological strategy in human adrenocortical carcinoma cell lines

“…The mechanism underlying the cytotoxic effect of Pg on TVBF-7, seemed to be linked to an increase in LC3-II levels, representing the activation of autophagy. The role of autophagy in the ACC context is challenging because it plays a double-edged role as a survival response to chemotherapeutic drugs, resulting in treatment failure, but also as an important mechanism underlying tumor cell suicide (Huang et al, 2019;Sousa et al, 2022;Tompkins et al, 2019). The cytoprotective function of autophagy is activated in many circumstances by suppressing apoptosis and this evidence justifies the observation of an increase in the cell viability in TVBF-7 cells exposed to Pg.…”

Low PRKAB2 Expression Is Associated with Poor Outcomes in Pediatric Adrenocortical Tumors, and Treatment with Rottlerin Increases the PRKAB2 Level and Inhibits Tumorigenic Aspects in the NCI-H295R Adrenocortical Cancer Cell Line

“…Rottlerin activates AMPK at the phosphorylation and activation (dissociation of catalytic subunits) levels [ 16 ]. The activation of AMPK and the PI3K/AKT/mTOR pathway induces autophagy and apoptosis in cancer cells [ 17 ], including the NCI-H295R cell line [ 18 ]. However, AMPK deregulation in pediatric ACTs has not been studied yet.…”