Although cancer cell metabolism was mainly considered to rely on glycolysis, with the concomitant impairment of mitochondrial metabolism, it has recently been demonstrated that several tumor types are sustained by oxidative phosphorylation (OXPHOS). In this context, endogenous fatty acids (FAs) deriving from lipolysis or lipophagy are oxidised into the mitochondrion, and are used as a source of energy through OXPHOS. Because the electron transport chain is the main source of ROS, cancer cells relying on fatty acid oxidation (FAO) need to be equipped with antioxidant systems that maintain the ROS levels under the death threshold. In those conditions, ROS can act as second messengers, favouring proliferation and survival. Herein, we highlight the different responses that tumor cells adopt when lipid catabolism is augmented, taking into account the different ROS fates. Many papers have demonstrated that the pro- or anti-tumoral roles of endogenous FA usage are hugely dependent on the tumor type, and on the capacity of cancer cells to maintain redox homeostasis. In light of this, clinical studies have taken advantage of the boosting of lipid catabolism to increase the efficacy of tumor therapy, whereas, in other contexts, antioxidant compounds are useful to reduce the pro-survival effects of ROS deriving from FAO.

The term autophagy identifies several mechanisms that mediate the degradation of intracellular and extracellular components via the lysosomal pathway. Three main forms of autophagy exist, namely macroautophagy, chaperone-mediated autophagy, and endosomal microautophagy, which have distinct mechanisms but share lysosomes as the final destination of their cargo. A basal autophagic flux is crucial for the maintenance of cellular homeostasis, being involved in the physiological turnover of proteins and organelles. Several stressors, including nutrient shortage and genotoxic and oxidative stress, increase the autophagic rate, which prevents the accumulation of damaged and potentially harmful cell components, thus preserving cell viability. In this context, several studies have highlighted the role of MAPKs, serine–threonine kinases activated by several stimuli, in linking oxidative stress and autophagy. Indeed, several oxidative stressors activate autophagy by converging on MAPKs, directly or indirectly. In this regard, the different transcription factors that bridge MAPKs and autophagic activation are here described. In this review, we summarize the current knowledge regarding the regulation of autophagy by MAPK, including the atypical ones, with a particular focus on the regulation of autophagy by oxidative stress.

Alteration of lysosomal homeostasis is common in cancer cells, which often feature an enlarged and peripheral distributed lysosomal compartment and the overexpression of cathepsins. These alterations accelerate the production of building blocks for the de novo synthesis of macromolecules and contribute to the degradation of the extracellular matrix, thus contributing to tumor growth and invasion. At the same time, they make lysosomes more fragile and more prone to lysosomal membrane permeabilization, a condition that can cause the release of proteases into the cytosol and the activation of cell death. Therefore, lysosomes represent a weak spot of cancer cells that can be targeted for therapeutic purposes. Here, we identify a novel role of the kinase JNK as keeper of lysosomal stability in hepatocellular carcinoma cells. JNK inhibition reduces the stability of LAMP2A, a lysosomal membrane protein responsible for the stability of the lysosomal membrane, promoting its degradation by the proteasome. LAMP2A decrease enhances the lysosomal damage induced by lysosomotropic agents, ultimately leading to cell death. The effect is cancer-specific, as JNK inhibition does not decrease LAMP2A in non-tumoral liver cells and does not alter their sensitivity to lysosomotropic drugs. Our finding on the new role of JNK as cancer-specific keeper of lysosomal homeostasis lays the ground for future evaluation of the efficacy of the combination of JNK inhibition and lysosomotropic agents as a potential therapeutic strategy in hepatocellular carcinoma.

Cancer cells rewire their metabolism to sustain the high proliferative rate. Metabolism is therefore a common vulnerability of cancer cells, successfully exploited for therapeutic purposes. Intrinsic tumor characteristics and adaptive responses of cancer cells can however reduce the short and long-term efficacy of such a strategy. Understanding the determinants of therapy response and the mechanisms of chemoresistance is crucial to maximize therapy efficacy. In cancer, lysosomes undergo massive changes in their localization, size, and composition that support tumor progression. Additionally, lysosomes are one of the crucial drivers of chemoresistance via the drug sequestration or by facilitating adaptations to stress conditions. In the last decades, several reports have shown that lysosomal membrane proteins, such as the lysosome-associated membrane proteins 1 and 2 (LAMP1 and LAMP2), are deregulated in different cancer types and their expression has been correlated to drug efficacy. We performed an in silico gene essentiality and drug sensitivity screenings, revealing that LAMP2 expression is one of the determinants of resistance to inhibitors of de novo purine synthesis. In vitro experiments confirmed the in silico data and also showed that purine synthesis inhibitors trigger a ROS- and transcriptional-dependent increase of LAMP2. Our results identify the upregulation of LAMP2 expression as an adaptive response to purine synthesis inhibition to preserve cell viability and, in those tumors showing high LAMP2 levels, could also be an indicator of intrinsic resistance to these drugs that may be taken into consideration during the selection of the most appropriate therapy.

Hepatocellular carcinoma (HCC) accounts for approximately 90% of liver cancer cases. Few therapeutic options are available for HCC patients due to intrinsic drug resistance or the low efficacy of conventional chemotherapeutic drugs, including genotoxic agents. We previously demonstrated that adipose triglyceride lipase (ATGL) is downregulated in HCC and shows anti-neoplastic activity by affecting sensitivity to different therapeutic approaches. On the basis of this evidence, we assessed the contribution of ATGL activity to the modulation of the DNA damage response induced by genotoxic drugs. We modulated ATGL expression via overexpression and silencing in the presence of etoposide and doxorubicin, which are genotoxic drugs. The catalytic activity of ATGL was abrogated by a selective inhibitor (ATGListatin) or the overexpression of the ATGL catalytic mutant. To assess the DNA damage response, we evaluated the phosphorylation of H2AX histones and the post-translational modifications of p53. The sensitivity to genotoxic drugs was assessed by analyzing cell viability and molecular markers associated with cell cycle arrest and cell death. Our results demonstrate that ATGL enhances DNA damage in HCC cells in response to genotoxic stimuli. The underlying molecular mechanism involves ATGL-mediated activation of PPARα/p300 signaling. As a result, we observed an imbalance in p53 acetylation/phosphorylation status that restrains cell cycle arrest and DNA damage repair while promoting apoptotic cell death. In line with the in vitro findings, bioinformatic analyses revealed a strong correlation between ATGL and the PPARα/p300 axis and further demonstrated an enrichment of gene sets associated with cell cycle regulation and DNA damage response in ATGL-high HCC. In conclusion, ATGL levels can be used as a predictive marker of HCC sensitivity to genotoxic insults. The activation of this lipase, or downstream molecular signaling, may thus be exploited to increase the efficacy of chemotherapeutic treatments in HCC.