br Autophagy is involved in a variety of cellular mechanisms
Autophagy is involved in a variety of cellular mechanisms, each of which in-hibits tumor progression by activating multiple molecular pathways.
Levine, 2008; Liu and Levine, 2015). The high level of genetic in-stability in cancer U73122 allows accumulation of spontaneous mutations and epigenetic modifications, which in turn rendered cells resistant to PCD mechanisms (Ferguson et al., 2015).
Several factors such as energy status (AMP/ATP levels), DNA da-mage or various stress conditions determine the fate of a cell regarding to survival, death or senescence (J. Su et al., 2015, Z. Su et al., 2015). Despite the widely accepted survival-supportive role of autophagy, in-creased autophagosome formation may also lead to apoptotic cell death (Eberhart et al., 2014; Gozuacik and Kimchi, 2004). Therefore, autop-hagy can serve as a cell death mechanism and contribute with apoptosis in tumorigenesis. Recent findings also suggest an inter-connected net-work of components involved in regulation of apoptosis and autophagy (Oral et al., 2016; Fulda and Koegel, 2015). Consequently, data in-dicates that autophagic cell death function as a tumor-suppressor me-chanism by coordinative action with other PCD mechanisms.
A member of anti-apoptotic proteins BCL-2 is highly expressed in various cancers and associated with the resistance to chemo- and radio-therapeutic approaches (Huang, 2000). BCL-2 is identified as negative regulator of Beclin-1 (Oberstein et al., 2007) and therefore, BCL-2 and Beclin-1 interaction is one of the critical determinant for autophagy and/or apoptosis activation in various cancer cells (Marquez and Xu, 2012; Akar et al., 2008; Lima et al., 2004). For example, overexpression of Beclin-1 in human laryngeal squamous carcinoma cells cause sig-nificant decrease in cell proliferation and promotes apoptotic cell death (Wan et al., 2018). The inhibitory role of Beclin-1 on cell proliferation was shown in diﬀerent types of cancer including, tongue squamous cell carcinoma (Hu et al., 2016), breast cancer (Wang and Feng, 2015), cervix cancer (Sun et al., 2011), lung cancer (Wang et al., 2013), glioblastoma (Huang et al., 2014a), squamous cell carcinoma cell lines (Weng et al., 2014), HCC (Zhao et al., 2014) colorectal cancer (Liu et al., 2017) and pancreas cancer (Li et al., 2013).
Tumor suppressive function of Beclin-1 is not limited to itself but also supported by the identification of its mediators involved in tu-morigenesis. A major Beclin-1 positive mediator, UVRAG is mutated in various human cancer cell lines (Goi et al., 2003; Kim et al., 2008). UVRAG-mediated activation of BECLIN1-PI (3) KC3 complex was shown to promote autophagy contributing to suppression of cell pro-liferation and tumorigenicity in human colon cancer cells (Liang et al., 2006).
JNK (c-Jun N-terminal kinase) is a member of the MAPK (mitogen-activated protein kinase) family that regulates a wide range of biolo-gical processes including tumorigenesis. JNK1-mediated phosphoryla-tion of BCL-2 stimulated starvation-induced autophagy through dis-ruption of BCL-2/Beclin-1 interaction (Wei et al., 2008). As an additional connection, autophagy is inhibited by the ER-localized BCL-2 through IRE1/JNK/Beclin-1 in breast cancer cells (Cheng et al., 2014). Moreover, Neuronal JNK1 was able to suppress autophagy by blocking FOXO1-mediated transcriptional activation of BNIP3 highlighting the cellular requirements of autophagy to survive (Xu et al., 2011). In ad-dition to JNK1, DAPK also phosphorylated Beclin-1 and disrupted the interaction of Beclin-1 with BCL-2 and BCL-XL, which in turn led to stimulation of autophagy (Zalckvar et al., 2009). DAPK1, a Ca2+/Cal-modulin-dependent Ser/Thr kinase, suppressed tumor growth and me-tastasis by promoting apoptosis and autophagy (Bialik and Kimchi, 2006; Huang et al., 2014a).
Another critical Ser/Thr kinase, ULK1 (Unc51-like kinase, hATG1), is phosphorylated and negatively regulated by mTORC1 mediates au-tophagy activation therefore inhibited cell proliferation in response to nutrient deprivation (Jung et al., 2011). Transcriptional activation of ULK1/2 by p53 resulted in elevated autophagic activity leading to au-tophagic cell death (Gao et al., 2011). ULK1/2 were shown to be downregulated in all grades of glioma suggesting that inhibition of autophagy by ULK1/2 downregulation is essential for astrocyte trans-formation and tumor progression (Shukla et al., 2014). These findings suggested that ULK1/2 upregulation contributed to tumor suppression European Journal of Pharmaceutical Sciences 134 (2019) 116–137
activity in mammalian cells through activation of autophagic cell death. Since autophagy has widespread influence on a number of biolo-gical pathways, this mechanism could inhibit cell proliferation by controlling cell cycle regulation. For example, enhanced autophagic activity was associated with cell cycle arrest at G2/M phase and in-duced death in pancreas cancer cells (Zhu and Bu, 2017). Correlatively, metformin-induced autophagic activity resulted in G0/G1 cell cycle arrest and inhibited cell proliferation in myeloma by targeting AMPK and mTORC (Zhu and Bu, 2017). As another example, elevated au-tophagic activity resulted in cell cycle arrest at G0/G1 phase and sub-sequent cell death in cervical cancer (Gao et al., 2018). Similarly, a natural product magnolin activated autophagy, caused cell cycle arrest through interefering LIF/Stat-3/Mcl-1 axiss and subsequently sup-pressed cell growth (Yu et al., 2018). Another natural product curcumin restricted tumor growth by regulating senescence and autophagy link in vivo and in vitro in colon cancer (Mosieniak et al., 2012). Autophagy has also been proposed to contribute to oncogene-induced senescence in cell-type dependent manner (Vicencio et al., 2008). For example, both autophagy and senescence were shown to be able to suppress self-renewal capacity in breast tumor cells exposed to DNA damage-indu-cing agent, doxorubicin (Di et al., 2016). Silencing either ATG5 or ATG7 suppressed oncogene-induced senescence in primary human melanocytes or human diploid fibroblasts (HDFs) (Liu et al., 2014; Young et al., 2009). Accordingly, transient overexpression of ULK3 reduced the proliferative potential of HDFs (Young et al., 2009). In-terestingly, chemical or genetic inhibition of autophagy prevented se-