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Dichotomous role of autophagy in cancer

Amin Arif
Amin Arif
, 
Muhammad Babar Khawar
Muhammad Babar Khawar
, 
Rabia Mehmood
Rabia Mehmood
, 
Muddasir Hassan Abbasi
Muddasir Hassan Abbasi
 e 
Nadeem Sheikh
Nadeem Sheikh
   | 30 giu 2022
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Article Category: Review
Pubblicato online: 30 giu 2022
Pagine: 111 - 120
DOI: https://doi.org/10.2478/abm-2022-0014
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© 2022 Amin Arif et al., published by Sciendo
This work is licensed under the Creative Commons Attribution 4.0 International License.

Figure 1

Schematic of autophagic routes. (A) Macroautophagy (commonly named autophagy): the autophagosome comprising several cytosolic polypeptides and proteins merges with lysosomes; subsequently, the autophagosomal content is digested by the lysosomal enzymes. (B) Microautophagy: the cytoplasmic elements directly enclosed by the inward pinching of lysosomal membrane. (C) CMA: the selective components move toward the lysosome after intermingling with the chaperone HSC70 and degrade in the lysosome. Created with BioRender.com. Academic License QJ23ZNIZN0. CMA, chaperone-mediated autophagy; PAS, preautophagosomal structure; HSC70, heat shock cognate 70 chaperones; LAMP2A, lysosome-associated membrane glycoprotein type 2A.
Schematic of autophagic routes. (A) Macroautophagy (commonly named autophagy): the autophagosome comprising several cytosolic polypeptides and proteins merges with lysosomes; subsequently, the autophagosomal content is digested by the lysosomal enzymes. (B) Microautophagy: the cytoplasmic elements directly enclosed by the inward pinching of lysosomal membrane. (C) CMA: the selective components move toward the lysosome after intermingling with the chaperone HSC70 and degrade in the lysosome. Created with BioRender.com. Academic License QJ23ZNIZN0. CMA, chaperone-mediated autophagy; PAS, preautophagosomal structure; HSC70, heat shock cognate 70 chaperones; LAMP2A, lysosome-associated membrane glycoprotein type 2A.

Figure 2

Schematic of macroautophagy flux. Autophagy starts with the development of a phagophore followed by the nucleation and elongation controlled by a class III PI3K complex and subsequently enclosure of cytoplasmic contents or organelles to form an autophagosome. The autophagosome then merges with a lysosome to develop into an autophagolysosome, the ultimate site for degradation and recycling. mTOR negatively controls autophagic flux, and it is inhibited by rapamycin and AZD8055 to induce autophagy. Beclin-2 also negatively controls autophagy by inhibiting the PI3K complex, and obatoclax and gossypol inhibit Beclin-2. 3-Methyladenine and wortmannin are early-stage inhibitors that hinder autophagy by negative control of the class III PI3K, and chloroquine, hydroxychloroquine, and biflomycin A are late-stage inhibitors that block the autophagic flux by interfering with the lysosome directly. Created with BioRender.com. Academic License DS23ZNI6O2. mTOR, mammalian targets of rapamycin; PI3K, phosphatidylinositol 3-kinase; CQ, chloroquine; HCQ, hydroxychloroquine.
Schematic of macroautophagy flux. Autophagy starts with the development of a phagophore followed by the nucleation and elongation controlled by a class III PI3K complex and subsequently enclosure of cytoplasmic contents or organelles to form an autophagosome. The autophagosome then merges with a lysosome to develop into an autophagolysosome, the ultimate site for degradation and recycling. mTOR negatively controls autophagic flux, and it is inhibited by rapamycin and AZD8055 to induce autophagy. Beclin-2 also negatively controls autophagy by inhibiting the PI3K complex, and obatoclax and gossypol inhibit Beclin-2. 3-Methyladenine and wortmannin are early-stage inhibitors that hinder autophagy by negative control of the class III PI3K, and chloroquine, hydroxychloroquine, and biflomycin A are late-stage inhibitors that block the autophagic flux by interfering with the lysosome directly. Created with BioRender.com. Academic License DS23ZNI6O2. mTOR, mammalian targets of rapamycin; PI3K, phosphatidylinositol 3-kinase; CQ, chloroquine; HCQ, hydroxychloroquine.

Autophagy regulators used in cancer therapy

Autophagy regulator Type Mode of action References
3-Methyladenine Inhibitor P13K inhibitors Upregulation of p62 protein expression [60, 70, 71, 72]
Wortmannin Inhibit phagosome formation [70, 73, 74]
LY294002 Promote apoptosis [71, 75]
Chloroquine Lysosome inhibitors Prevent acidification [76]
Hydroxychloroquine Inhibit autophagosome accumulationInhibit the formation of autolysosome [77, 78, 79, 80]
Bafilomycin A Inhibit autophagic degradation [81]
Tioconazol ATG inhibitors Inhibit phagophore elongation [82]
FMK-9a Inhibit autophagosome fusion [83]
Rapamycin Inducer mTOR inhibitors Prevent inactivation of ULK1 phosphorylation [84]
AZD8055 Activate or induce autophagyInduction of apoptosisCell cycle arrest [85, 86]
Vitamin D Natural products or mTOR inhibitors Increase intestinal calcium absorptionInduce expression of proapoptotic proteinsInduces an autophagic transcriptional signatureInduce autophagosome formation [87, 88]
Resveratrol Induce apoptotic cell deathSuppress growth of cancer cell [89]
Curcumin Induce apoptosisInhibit phosphorylation of AKT [90]
Obatoclax BH3 Mimetics or Beclin-2 inhibitors Bcl-2 inhibition [91, 92]
Gossypol ROS productionAutophagic-mediated necroptosis [93]
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