Dear Editor,
We have read this article published in the Journal of Investigative Medicine with great interest. In this paper, Radovanovic et al 1 investigated macroautophagy (hereafter autophagy) and apoptosis focusing on the regulatory roles of 5'-adenosine monophosphate-activated protein kinase (AMPK) and mechanistic target of rapamycin (mTOR) in clear cell renal cell carcinoma (ccRCC). They showed autophagy induction (uncoordinated protein 51-like kinase 1 (ULK1) phosphorylation, LC3 lipidation and p62 degradation) in ccRCC compared with normal renal cells. Interestingly, the active form of AMPK was shown to be lower in ccRCC whereas the phosphorylated form of initiation factor 4E-binding protein 1 (4EBP1), the substrate of mTOR, was increased. Therefore, they concluded that autophagy was executed independent of the AMPK and mTOR pathway.
Autophagy is responsible for degradation and recycling of impaired organelles and cytosolic misfolded proteins to maintain cellular function.2 The autophagy process is executed by autophagy related (ATG) proteins. mTOR is one of the key regulators of autophagy by negatively controlling the autophagy initiation complex, ULK, under normal conditions and energy abundance.3 The AMPK pathway is energy sensitive which leads to mTOR inhibition and autophagy induction.4
Autophagy components are subject to various post-translational regulatory modifications, such as phosphorylation, ubiquitination and acetylation. For instance, autophagy can be stimulated by death associated protein kinase 1 (DAPK1)- and c-Jun N-terminal kinase (JNK)-mediated phosphorylation of BECLIN1 and its inhibitory binding partner, Bcl2, respectively.5 Tumor necrosis factor receptor (TNFR)-associated factor 6 (TRAF6) causes ULK1 ubiquitination during autophagy induction, facilitating its kinase activity. TRAF6 is also involved in the regulatory mechanism between the Wnt/β-catenin signaling pathway and autophagy.6 7 Moreover, ATG proteins have been shown to play roles in cellular processes other than autophagy including autophagy-independent apoptosis induction.5 8
The dual role of autophagy as a pro- and anti-cancer pathway has been investigated extensively. Autophagy can support the energy requirement of cancer cells for growth and metastasis.5 9 Conversely, induction of autophagy has been shown to restrain the growth and progression of tumor cells in several cancers, including breast cancer, hepatocellular carcinoma and RCC.10–12 In line with this, a study by Li et al 13 showed the anti-metastatic effect of autophagy induction in an adenocarcinoma; renal cell (ACNH) and 786-O RCC cell model-based study. In contrast to the work by Radovanovic and colleagues, this study demonstrated that the AMPK/mTOR pathway was involved in autophagy induction.13 This discrepancy might be due to the fact that, in the study by Radovanovic et al, whole tumor tissue was used for total cell lysate preparation, which may also contain a heterogeneous population of cancer cells and renal epithelial cells (figure 1).14 15 Therefore, the AMPK/mTOR axis in autophagy activation requires further investigation and we propose that assessing and fully understanding the functional impact of non-canonical autophagy regulators in ccRCC might provide novel cancer treatment strategies and discover the roles of unidentified regulatory proteins in the autophagy pathway.
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Contributors SL prepared the draft of the manuscript, performed the literature search and prepared the draft figure. SG made the final edit, led and supervised the team and prepared the final manuscript.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.