br Autophagy regulates stem cell
3.1.5. Autophagy regulates stem cell maintenance
The ability of the stem M3814 (nedisertib) to self-renew and diﬀerentiate into several types of cells are bearing great importance for oncogenic pro-cesses as well as development and tissue renewal. Tumor-initiating cells share some characteristics with stem cells and are capable of self- European Journal of Pharmaceutical Sciences 134 (2019) 116–137
renewal and diﬀerentiation (Visvader and Lindeman, 2012). Several lines of evidence indicated that autophagy functions as an important mechanism in quality control and maintenance of cellular homeostasis in stem cells (Guan et al., 2013). Depletion of ATG7 in murine hema-topoietic stem cells (HSCs) increased neoplastic features by altering the number of bone marrow progenitor cells (Mortensen et al., 2011). In another study, tissue-specific deletion of FIP200 correlated with severe anemia and prenatal lethality in hematopoietic stem cells (F. Liu et al., 2010). In line with this, FIP200 deletion in murine neuronal stem cells (NSCs) interfered with postnatal neuronal diﬀerentiation (Wang et al., 2013). As another example of autophagy-mediated regulation of stem cells, it has been reported that autophagic activity supported breast cancer stem cell maintenance through regulation of IL6 secretion (Maycotte et al., 2015).
3.2. Autophagy as a pro-oncogenic mechanism
In addition to its tumor suppressive role, autophagy also contributes to malignant transformation and/or metastatic cascade by supporting cancer cells under stress conditions (e.g. exposure to metabolic, hy-poxic, genotoxic, and oxidative stress) or tumor microenvironment (e.g. survival in the circulatory system, oxygen and glucose deprivation in solid tumors). Evidence also suggested that autophagy provides re-sistance to cancer cells against chemo-/radio-therapies and cell death. Pro-oncogenic function of autophagy is summarized in Fig. 3.
3.2.1. Autophagy supplies nutrients and energy to cancer cells
In cells, it is well established that glucose is primary nutrient source for energy production and constant glucose supply is required for ATP production. In cancer cells, increased aerobic glycolysis was first re-ported by Warburg in the 1920s. Conversion of glucose to lactate in aerobic conditions also results in microenvironmental acidosis there-fore cancer cells must adopt resistance to acid-induced cell toxicity. Malignant cells with high glycolytic capacity also displayed resistance to acidosis and therefore gain growth advantage over the normal cells for unconstrained proliferation, invasion and tumorigenesis (Gatenby and Gillies, 2004). Malignant transformation is generally accompanied with metabolic changes, including elevated glucose uptake to sustain anabolic reactions and antioxidant defense and increased mitochondrial respiration to supply high-energy demand and several amino acids (Hanahan and Weinberg, 2011).
The PI3K-AKT-mTOR pathway plays a major role in regulation of
Fig. 3. Tumor promoting role of autophagy.
Autophagy contributes to tumorigenesis in a variety of stages ranging from proliferation to metastasis and invasion as well as sustain its improvement by providing resistance to death mechanisms.
aerobic glycolysis in cancer cells (Makinoshima et al., 2015). Inhibition of PI3K limited glucose uptake and glycolysis by blocking GLUT1 function (Barnes et al., 2005). AKT and c-MYC, positive regulators of essential glycolytic genes have shown to possess diﬀerential and com-plementary eﬀects in driving aerobic glycolysis (Fan et al., 2010). Ad-ditionally, c-MYC was also implicated in regulation of glutamine me-tabolism under the control of SIRT1 in order to reach the high demand for energy generation and biosynthesis in cancer cells (Ren et al., 2017). In order to meet with altered metabolic requirements of cancer cells, autophagy maintained a critical role in these adaptation period by providing required energy and biomolecules through recycling of mo-lecules and/or organelles (Galluzzi et al., 2015).
Normal fibroblast cells neighboring tumor cells acquire a phenotype known as the cancer-associated fibroblasts (CAFs), where autophagic activity supported the high demand of cancer cells for the energy and nutrient support (Martinez-Outschoorn et al., 2011). Injection of CAFs overexpressing pro-autophagic molecules together with cancer cells into mice promoted tumor growth and favored for lung metastasis (Yang et al., 2015). Furthermore, autophagic activity in apoptosis-de-ficient tumor cells was correlated with the survival of cancer cells under stress conditions (Degenhardt et al., 2006). Interestingly, autophagy has also been implicated in the metabolic control of hematopoietic stem cells during throphic factor deprivation (Yang et al., 2015).
3.2.2. Autophagy mediates adaptation to hypoxia, oxidative stress and DNA damage