**4.3 Autophagic cell death**

Autophagic cell death or programmed cell death (PCD) type II is a constitutively active self-degradative process of cellular constituents [86]. It is responsible for maintaining cellular homeostasis [87] under stressful conditions, such as nutrient

starvation, hypoxia, growth factor insufficiency, acidosis, or drug exposure [87]. Autophagy begins with an isolation membrane that engulfs intracellular cargo [88], degraded by lysosomal acid proteases. These lysosomal permeases and transporters export amino acids and other by-products of degradation back out to the cytoplasm, where they can be reused for building macromolecules and for metabolism [88]. Autophagy is regulated by the target of rapamycin (TOR) kinase, which is regulated by some effectors [89]. Upstream of TOR, activation of AMP-activated protein kinase AMPK in response to low ATP levels. Downstream, reduced Akt activity represses TOR kinase [89] and induces autophagy, stimulating catabolism and reducing its growth. Cholesterol depletion induced by statins produces inactivation of mTOR, which then induces autophagy [18] and also can promote cancer cell death after stimulation of ERK1/2 and Akt pathways [58]. In sarcomas, autophagy plays an important role in the pro-survival response to therapies and stress, and in the therapeutic resistance of sarcoma [87]. The cell cycle arrest and apoptosis process start with the GGPP depletion, which leads to a disrupted RhoA function, which activates AMPK and consequently inactivates mTOR [84]. Finally, statin accumulated p53 at the nucleus and induces autophagy through phosphorylation of HMGCoAR [59].
