bims-apauto 2022-05-08 papers

Issue of 2022–05–08
four papers selected by
Su Hyun Lee, Seoul National University

J Cell Biochem. 2022 May 01.

Differential effects of 5-fluorouracil and oxaliplatin on autophagy in chemoresistant colorectal cancer cells.

Vilmante Zitkute, Egle Kukcinaviciute, Violeta Jonusiene, Vytaute Starkuviene, Ausra Sasnauskiene.

Macroautophagy (hereafter autophagy) is one of the adaptive pathways that contribute to cancer cell chemoresistance. Despite the fact that autophagy can both promote and inhibit cell death, there is mounting evidence that in the context of anticancer treatment, it predominantly functions as a cell survival mechanism. Therefore, silencing of key autophagy genes emerges as a potent strategy to reduce chemoresistance. Though the importance of autophagy in chemoresistance is established, the changes in autophagy in the case of acquired chemoresistance are poorly understood. In this study, we aimed to determine the changes of autophagy in the cellular model of acquired chemoresistance of colorectal cancer cell lines HCT116 and SW620, induced by 5-fluorouracil (5-FU) or oxaliplatin (OxaPt) treatment, and determine the susceptible factors for autophagy inhibition. Our results demonstrate that in the context of autophagy, 5-FU and OxaPt have different effects on HCT116 and SW620 cell lines and their chemoresistant sublines. 5-FU inhibits autophagic flux, while changes in the flux after OxaPt treatment are cell type- and dose-dependent, inducing autophagy reduction or increase. The chemoresistant subline of HCT116 cells derived by OxaPt differs from the subline derived by 5-FU treatment - it responds to OxaPt by upregulating ATG7 protein level and autophagic flux, in contrast to downregulation in cells derived by 5-FU. Moreover, 5-FU and OxaPt treatments significantly modulate protein levels of core-autophagy proteins ATG7 and ATG12. The potential effects of 5-FU and OxaPt on ATG protein levels should be taken into account to reduce chemoresistance by applying small interferingRNAs, targeting ATG proteins.

Keywords: 5-fluorouracil; ATG12; ATG7; autophagy; chemoresistance; colorectal cancer; oxaliplatin

DOI: https://doi.org/10.1002/jcb.30267

Life Sci. 2022 Apr 30. pii: S0024-3205(22)00295-8. [Epub ahead of print] 120595

Mechanisms of autophagy and mitophagy in skeletal development, diseases and therapeutics.

Jyotirmaya Behera, Jessica Ison, Ashish Tyagi, Gabriel Mbalaviele, Neetu Tyagi.

Autophagy is a highly evolutionarily conserved process in the eukaryotic cellular system by which dysfunctional organelles are selectively degraded through a series of processes of lysosomal activity and then returned to the cytoplasm for reuse. All cells require this process to maintain cellular homeostasis and promote cell survival during stress responses such as deprivation and hypoxia. Osteoblasts and osteoclasts are two cellular phenotypes in the bone that mediate bone homeostasis. However, an imbalance between osteoblastic bone formation and osteoclastic bone resorption contributes to the onset of bone diseases. A recent study suggests that autophagy, mitophagy, and selective mitochondrial autophagy may play an essential role in regulating osteoblast differentiation and osteoclast maturation. Autophagic activity dysregulation alters the equilibrium between osteoblastic bone creation and osteoclastic bone resorption, allowing bone disorders like osteoporosis to develop more easily. The current review emphasizes the role of autophagy and mitophagy and their related molecular mechanisms in bone metabolic disorders. In the current review, we emphasize the role of autophagy and mitophagy as well as their related molecular mechanism in bone metabolic disorders. Furthermore, we will discuss its potential as a new molecular target for the treating of metabolic bone disease and future application in therapeutic translational research.

Keywords: Autophagy; Epigenetics; Mitophagy; Osteoporosis; miRNA regulation

DOI: https://doi.org/10.1016/j.lfs.2022.120595

EMBO J. 2022 May 02. e109460

Structural basis for feedforward control in the PINK1/Parkin pathway.

Véronique Sauvé, George Sung, Emma J MacDougall, Guennadi Kozlov, Anshu Saran, Rayan Fakih, Edward A Fon, Kalle Gehring.

PINK1 and parkin constitute a mitochondrial quality control system mutated in Parkinson's disease. PINK1, a kinase, phosphorylates ubiquitin to recruit parkin, an E3 ubiquitin ligase, to mitochondria. PINK1 controls both parkin localization and activity through phosphorylation of both ubiquitin and the ubiquitin-like (Ubl) domain of parkin. Here, we observed that phospho-ubiquitin can bind to two distinct sites on parkin, a high-affinity site on RING1 that controls parkin localization and a low-affinity site on RING0 that releases parkin autoinhibition. Surprisingly, ubiquitin vinyl sulfone assays, ITC, and NMR titrations showed that the RING0 site has higher affinity for phospho-ubiquitin than phosphorylated Ubl in trans. We observed parkin activation by micromolar concentrations of tetra-phospho-ubiquitin chains that mimic mitochondria bearing multiple phosphorylated ubiquitins. A chimeric form of parkin with the Ubl domain replaced by ubiquitin was readily activated by PINK1 phosphorylation. In all cases, mutation of the binding site on RING0 abolished parkin activation. The feedforward mechanism of parkin activation confers robustness and rapidity to the PINK1-parkin pathway and likely represents an intermediate step in its evolutionary development.

Keywords: Parkinson's disease; autophagy; mitophagy; open-loop control; ubiquitin

DOI: https://doi.org/10.15252/embj.2021109460

Trends Cell Biol. 2022 Apr 29. pii: S0962-8924(22)00090-3. [Epub ahead of print]

Protein kinase Cλ/ι in cancer: a contextual balance of time and signals.

Jorge Moscat, Juan F Linares, Angeles Duran, Maria T Diaz-Meco.

Nononcogenic cancer drivers often impinge on complex signals that create new addictions and vulnerabilities. Protein kinase Cλ/ι (PKCλ/ι) suppresses tumorigenesis by blocking metabolic pathways that regulate fuel oxidation and create building blocks for the epigenetic control of cell differentiation. Reduced levels of PKCλ/ι unleash these pathways to promote tumorigenesis, but the simultaneous activation of the STING-driven interferon cascade prevents tumor initiation by triggering immunosurveillance mechanisms. However, depending on the context of other signaling pathways, such as WNT/β-catenin or PKCζ, and timing, PKCλ/ι deletion can promote or inhibit tumorigenesis. In this review, we discuss in detail the molecular and cellular underpinnings of PKCλ/ι functions in cancer with the perspective of the crosstalk between metabolism and inflammation in the tumor microenvironment.

Keywords: autophagy; cancer; interferon; metabolism; protein kinase C; tumor microenvironment

DOI: https://doi.org/10.1016/j.tcb.2022.04.002