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  • However there are studies revealing the dark side of autopha

    2023-09-18

    However, there are studies revealing the “dark side” of autophagy at later stages in cancers, when oncogenes (mainly K-ras and B-raf) are activated and/or tumour suppressors such as PTEN and p53 are inactivated. These studies are based on the use of GEMM and deletions of essential autophagy genes (ATG7 or ATG5) in K-rasG12D[38], [39] or B-rafV600E-driven cancers (primarily in melanoma, pancreas and lung cancers) [39], [40] (Fig. 1). These experimental models have great advantages respect to xenograft mice since they allow the study of cancer progression and the effects of autophagy deficiency only in tumour tissues of animals with an intact immune system. Guo et al. demonstrated that in the absence of an essential autophagy gene (ATG7) in tumour epithelial cells in GEMM expressing K-rasG12D in lung, the mice showed defective mitochondria and protein vx 809 leading to cancer cell growth arrest or cell death and more benign disease (oncocytoma) respect to control mice expressing Atg7 [39]. Histological analysis of benign oncocytoma revealed the presence of defective mitochondria and lipid accumulation since the absence of ATG7 impaired mitochondrial respiration and fatty acids oxidation. The explanation was that in K-rasG12D-driven lung cancer autophagy is essential to support metabolism and growth of tumour cells. In fact, Atg7 also suppresses p53 activation contributing to cancer cell growth and progression [38], [39]. A similar observation was revealed in the same context of lung carcinogenesis driven by B-rafV600E. Here, the authors demonstrated that the initial phenotype in the absence of ATG7 in GEMM expressing B-rafV600E consisted in Nrf2 defective antioxidant defence response driving initial steps of carcinogenesis. These mice showed benign lung oncocytoma characterized by defective mitochondria and altered metabolism, which finally compromised tumour growth. In fact, at a later time, the anticancer effect due to the absence of ATG7 became the dominant phenotype and the mice experienced lifespan extension and a reduction of tumour mass due to the same histological and metabolic alterations seen in K-rasG12D mutated lung cancer [41] (Fig. 1). B-raf mutations are also common in melanoma (80–90% cases), a tumour characterized by high levels of basal autophagy. Targeted therapy against this oncogenic alteration usually shows a limited efficacy and resistance is often developed. Using a mice model of B-rafV600E-driven melanoma, in the presence of PTEN tumour suppressor deletion, Xie et al. [40] studied the functional consequences of ATG7 deficiency. The absence of ATG7 prevented melanoma development, indicating an essential role of autophagy in cancer onset. The common phenotype, also seen in lung cancer, was the accumulation of autophagy substrates and growth defects which finally extended mice lifespan since cancer cells showed increased oxidative stress and senescence, which represent well-known barrier against carcinogenesis [42]. The data reported above referring to solid tumours are corroborated by parallel results in blood cancers. In fact, recent studies confirm that autophagy contributes to block initial leukemogenesis for its crucial role in hematopoietic stem cells (HSC) maintenance, correct differentiation of myeloid and lymphoid progenitors and elimination of oncogenic proteins such as PML-RARα and BCR-ABL [43], [44]. Autophagy, at later stages, is always functionally linked to drug resistance. Deleting ATG7 gene or blocking the expression of the Ulk-1-interacting protein, FIP200, mice showed severe damaged in HSC with defective mitochondria and DNA damage followed by a lethal pre-leukemic phenotype [45], [46]. This observation was confirmed applying a different approach. Using human acute myeloid leukemia (AML) cells isolated from patients, the loss of ATG5 or ATG7 resulted in an impaired autophagic flux respect to normal HSC with the accumulation of damaged mitochondria and ROS increase, confirming the protective role of autophagy against leukemogenesis [47].