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The difficulty of early diagnosis and the development of drug resistance are two major barriers to the successful treatment of cancer. Autophagy plays a crucial role in several cellular functions, and its dysregulation is associated with both tumorigenesis and drug resistance. Unc-51-like kinase 1 (ULK1) is a serine/threonine kinase that participates in the initiation of autophagy. Many studies have indicated that compounds that directly or indirectly target ULK1 could be used for tumor therapy. However, reports of the therapeutic effects of these compounds have come to conflicting conclusions. In this work, we reviewed recent studies related to the effects of ULK1 on the regulation of autophagy and the development of drug resistance in cancers, with the aim of clarifying the mechanistic underpinnings of this therapeutic target.

MicroRNAs are small highly conserved noncoding RNAs that are widely expressed in multicellular organisms and participate in the regulation of various cellular processes including autophagy and viral replication. Evidently, microRNAs are able to modulate host gene expression and thereby inhibit or enhance hepatitis B virus (HBV) replication. The miR‐99 family members are highly expressed in the liver. Interestingly, the plasma levels of miR‐99 family in the peripheral blood correspond with HBV DNA loads. Thus, we asked whether the miR‐99 family regulated HBV replication and analyzed the underlying molecular mechanism. Compared with primary hepatocytes, miR‐99 family expression was downregulated in hepatoma cells. Transfection of miR‐99a, miR‐99b, and miR‐100 markedly increased HBV replication, progeny secretion, and antigen expression in hepatoma cells. However, miR‐99 family had no effect on HBV transcription and HBV promoter activities, suggesting that they regulate HBV replication at posttranscriptional steps. Consistent with bioinformatic analysis and recent reports, ectopic expression of miR‐99 family attenuated IGF‐1R/Akt/mTOR pathway signaling and repressed insulin‐stimulated activation in hepatoma cells. Moreover, the experimental data demonstrated that the miR‐99 family promoted autophagy through mTOR/ULK1 signaling and thereby enhanced HBV replication. In conclusion, the miR‐99 family promotes HBV replication posttranscriptionally through IGF‐1R/PI3K/Akt/mTOR/ULK1 signaling‐induced autophagy.

Puerarin suppresses autophagy to alleviate cerebral ischemia/reperfusion injury, and accumulating evidence indicates that the AMPK-mTOR signaling pathway regulates the activation of the autophagy pathway through the coordinated phosphorylation of ULK1. In this study, we investigated the mechanisms underlying the neuroprotective effect of puerarin and its role in modulating autophagy via the AMPK-mTOR-ULK1 signaling pathway in the rat middle cerebral artery occlusion model of cerebral ischemia/reperfusion injury. Rats were intraperitoneally injected with puerarin, 50 or 100 mg/kg, daily for 7 days. Then, 30 minutes after the final administration, rats were subjected to transient middle cerebral artery occlusion for 90 minutes. Then, after 24 hours of reperfusion, the Longa score and infarct volume were evaluated in each group. Autophagosome formation was observed by transmission electron microscopy. LC3, Beclin-1 p62, AMPK, mTOR and ULK1 protein expression levels were examined by immunofluorescence and western blot assay. Puerarin substantially reduced the Longa score and infarct volume, and it lessened autophagosome formation in the hippocampal CA1 area following cerebral ischemia/reperfusion injury in a dose-dependent manner. Pretreatment with puerarin (50 or 100 mg/kg) reduced Beclin-1 expression and the LC3-II/LC3-I ratio, as well as p-AMPK and pS317-ULK1 levels. In comparison, it increased p62 expression. Furthermore, puerarin at 100 mg/kg dramatically increased the levels of p-mTOR and pS757-ULK1 in the hippocampus on the ischemic side. Our findings suggest that puerarin alleviates autophagy by activating the APMK-mTOR-ULK1 signaling pathway. Thus, puerarin might have therapeutic potential for treating cerebral ischemia/reperfusion injury.

The cyclin D binding Myb‐like Transcription Factor 1 (DMTF1) is a haploinsufficient tumor suppressor in various tumors. Alternative splicing generates a dominant negative, truncated version of full‐length DMTF1α, named DMTF1β. DMTF1β has so far been described as an oncogene in breast cancer development. However, a clear understanding of how DMTF1β contributes to carcinogenesis remains unknown. Analyzing DMTF1β protein expression in breast cancer cell lines, as well as a highly metastatic prostate cancer cell line, confirmed a positive correlation between DMTF1β expression and tumorigenic potential. Specifically, knocking down DMTF1β in aggressive MDA‐MB‐231 breast and PC3MPRO4 prostate cancer cells significantly reduced wound closure and tissue invasion. β‐specific interactome and RNA‐sequencing studies in DMTF1β overexpressing and knockdown cells, respectively, suggest that DMTF1β expression is associated with the autophagy recycling pathway. Depleting DMTF1β levels in cancer cells significantly decreased autophagic flux. Moreover, inhibiting autophagy led to decreased migration of DMTF1β expressing breast cancer cells. Mechanistically, DMTF1β protein interacts with and stabilizes the key autophagy protein ULK1. In conclusion, we identified a novel function for the alternatively spliced DMTF1 gene product in autophagy‐dependent cancer cell motility.

Drug resistance is an important factor for treatment failure of gastric cancer. N6‐methyladenosine (m6A) is the predominant mRNA internal modification in eukaryotes. The roles of m6A modification in drug resistance of gastric cancer remains unclear. In the present study, the m6A methylated RNA level was significantly decreased while the expression of m6A demethylase fat mass and obesity‐associated protein (FTO) was obviously elevated in cisplatin‐resistant (SGC‐7901/DDP) gastric cancer cells. Knockdown of FTO reversed cisplatin resistance of SGC‐7901/DDP cells both in vitro and in vivo, which was attributed to the inhibition of Unc‐51‐like kinase 1 (ULK1)‐mediated autophagy. Mechanistically, ULK1 expression was regulated in an FTO‐m6A‐dependent and YTHDF2‐mediated manner. Collectively, our findings indicate that the FTO/ULK1 axis exerts crucial roles in cisplatin resistance of gastric cancer. Knockdown of FTO reversed cisplatin resistance of SGC‐7901/DDP cells both in vitro and in vivo, which were attributed to the inhibition of ULK1 mediated‐autophagy. ULK1 expression was regulated in the FTO‐m6A dependent and YTHDF2‐mediated manner.

Autophagy is a process of self-degradation that enables the cell to survive when faced with starvation or stressful conditions. The mechanistic target of rapamycin (mTOR), also known as the mammalian target of rapamycin, plays a critical role in maintaining a balance between cellular anabolism and catabolism. mTOR complex 1 (mTORC1) was unveiled as a master regulator of autophagy since inhibition of mTORC1 was required to initiate the autophagy process. Evidence has emerged in recent years to indicate that mTORC1 also directly regulates the subsequent steps of the autophagy process, including the nucleation, autophagosome elongation, autophagosome maturation and termination. By phosphorylating select protein targets of the autophagy core machinery and/or their regulators, mTORC1 can alter their functions, increase their proteasomal degradation or modulate their acetylation status, which is a key switch of the autophagy process. Moreover, it phosphorylates and alters the subcellular localization of transcription factors to suppress the expression of genes needed for autophagosome formation and lysosome biogenesis. The purpose of this review article is to critically analyze current literatures to provide an integrated view of how mTORC1 regulates various steps of the autophagy process.

You J, Wang X. Cancer Manag Res. 2021;13:3827-3839. At the authors request, the Editor and Publisher of Cancer Management and Research wish to retract the published article. The authors have informed the journal that they are unable to provide the original data for the study and are unable to verify the findings after failing to reproduce the results. The Editor agreed with the decision to retract. We have been informed in our decision-making by our policy on publishing ethics and integrity and the COPE guidelines on retractions. The retracted article will remain online to maintain the scholarly record, but it will be digitally watermarked on each page as \"Retracted\". This retraction relates to this paper

In this study, the purpose of this study was to investigate the role of TNFAIP8 in gastric cancer (GC). The expression of TNFAIP8 was detected by RT‐PCR or western blot . TNFAIP8 was silenced or overexpressed in two cell lines. CCK‐8 assay, transwell assay and flow cytometry were used to analyse cell viability, cell invasion capability and apoptosis, respectively. Nude mice were inoculated with TNFAIP8 silencing or overexpressing cells to form transplanted tumours. HE staining and immunohistochemistry assay were performed to assess histopathological changes in tumours. We found that the mRNA and protein expression of TNFAIP8 were significantly up‐regulated in GC tumour tissues and cells compared with the normal counterparts. Overexpression of TNFAIP8 in GC cells increased cell viability, decreased apoptosis and promoted the cell migration ability. Meanwhile, increased expression of TNFAIP8 promoted autophagy, while inhibiting mTOR‐Akt‐ULK1 signal pathway. In conclusions, this study presents data that TNFAIP8 inhibits GC cells presumably by down‐regulating mTOR‐Akt‐ULK1 signal pathway and activating autophagy signal.

Background Diabetes and obesity are associated with muscle atrophy that reduces life quality and lacks effective treatment. Mesenchymal stromal cell (MSC)‐based therapy can ameliorate high fat‐diet (HFD) and immobilization (IM)‐induced muscle atrophy in mice. However, the effect of MSCs on muscle atrophy in type 2 diabetes mellitus (T2DM) and the potential mechanism is unclear. Here, we evaluated the efficacy and explored molecular mechanisms of human umbilical cord MSCs (hucMSCs) and hucMSC‐derived exosomes (MSC‐EXO) on diabetes‐ and obesity‐induced muscle atrophy. Methods Diabetic db/db mice, mice fed with high‐fat diet (HFD), mice with hindlimb immobilization (IM), and C2C12 myotubes were used to explore the effect of hucMSCs or MSC‐EXO in alleviating muscle atrophy. Grip strength test and treadmill running were used to measure skeletal muscle strength and performance. Body composition, muscle weight, and muscle fibre cross‐sectional area (CSA) was used to evaluate muscle mass. RNA‐seq analysis of tibialis anterior (TA) muscle and Western blot analysis of muscle atrophy signalling, including MuRF1 and Atrogin 1, were performed to investigate the underlying mechanisms. Results hucMSCs increased grip strength (P = 0.0256 in db/db mice, P = 0.012 in HFD mice, P = 0.0097 in IM mice), running endurance (P = 0.0154 in HFD mice, P = 0.0006 in IM mice), and muscle mass (P = 0.0004 in db/db mice, P = 0.0076 in HFD mice, P = 0.0144 in IM mice) in all models tested, with elevated CSA of muscle fibres (P < 0.0001 in db/db mice and HFD mice, P = 0.0088 in IM mice) and reduced Atrogin1 (P = 0.0459 in db/db mice, P = 0.0088 in HFD mice, P = 0.0016 in IM mice) and MuRF1 expression (P = 0.0004 in db/db mice, P = 0.0077 in HFD mice, P = 0.0451 in IM mice). MSC‐EXO replicated all these hucMSC‐mediated changes (P = 0.0103 for grip strength, P = 0.013 for muscle mass, P < 0.0001 for CSA of muscle fibres, P = 0.0171 for Atrogin1 expression, and P = 0.006 for MuRF1 expression). RNA‐seq revealed that hucMSCs activated the AMPK/ULK1 signalling and enhanced autophagy. Knockdown of AMPK or inhibition of autophagy with 3‐methyladenine (3‐MA) diminished the beneficial anti‐atrophy effects of hucMSCs or MSC‐EXO. Conclusions Our results suggest that human umbilical cord mesenchymal stromal cells mitigate diabetes‐ and obesity‐induced muscle atrophy via enhancing AMPK/ULK1‐mediated autophagy through exosomes, with implications of applying hucMSCs or hucMSC‐derived exosomes to treat muscle atrophy.