The Atg1/ULK1 complex plays a central role in starvation-induced autophagy, integrating signals from upstream sensors such as MTOR and AMPK and transducing them to the downstream autophagy pathway. Much progress has been made in the last few years in understanding the mechanisms by which the complex is regulated through protein-protein interactions and post-translational modifications, providing insights into how the cell modulates autophagy, particularly in response to nutrient status. However, how the ULK1 complex transduces upstream signals to the downstream central autophagy pathway is still unclear. Although the protein kinase activity of ULK1 is required for its autophagic function, its protein substrate(s) responsible for autophagy activation has not been identified. Furthermore, examples of potential ULK1-independent autophagy have emerged, indicating that under certain specific contexts, the ULK1 complex might be dispensable for autophagy activation. This raises the question of how the autophagic machinery is activated independent of the ULK1 complex and what are the biological functions of such noncanonical autophagy pathways.

https://www.tandfonline.com/doi/pdf/10.4161/auto.23323

The ULK1 complex: Sensing nutrient signals for autophagy activation

Macroautophagy/autophagy is a fundamental cellular degradation mechanism that maintains cell homeostasis, regulates cell signaling, and promotes cell survival. Its role in promoting tumor cell survival in stress conditions is well characterized, and makes autophagy an attractive target for cancer therapy. Emerging research indicates that autophagy also influences cancer metastasis, which is the primary cause of cancer-associated mortality. However, data demonstrate that the regulatory role of autophagy in metastasis is multifaceted, and includes both metastasis-suppressing and -promoting functions. The metastasis-suppressing functions of autophagy, in particular, have important implications for autophagy-based treatments, as inhibition of autophagy may increase the risk of metastasis. In this review, we discuss the mechanisms and context underlying the role of autophagy in metastasis, which include autophagy-mediated regulation of focal adhesion dynamics, integrin signaling and trafficking, Rho GTPase-mediated cytoskeleton remodeling, anoikis resistance, extracellular matrix remodeling, epithelial-to-mesenchymal transition signaling, and tumor-stromal cell interactions. Through this, we aim to clarify the context-dependent nature of autophagy-mediated metastasis and provide direction for further research investigating the role of autophagy in cancer metastasis.

https://www.tandfonline.com/doi/pdf/10.1080/15548627.2018.1450020

Mechanisms and context underlying the role of autophagy in cancer metastasis

The function of mitophagy in cancer is controversial. ULK1 is critical for induction of macroautophagy/autophagy and has a more specific role in mitophagy in response to hypoxia. Here, we show that ULK1 deficiency induces an invasive phenotype of breast cancer cells under hypoxia and increases osteolytic bone metastasis. Mechanistically, ULK1 depletion attenuates mitophagy ability during hypoxia. As a result, the accumulation of damaged, ROS-generating mitochondria leads to activation of the NLRP3 inflammasome, which induces abnormal soluble cytokines secretion, then promotes the differentiation and maturation of osteoclasts, and ultimately results in bone metastasis. Notably, phosphorylation of ULK1 by MAPK1/ERK2-MAPK3/ERK1 kinase triggers its interaction with BTRC and subsequent K48-linked ubiquitination and proteasome degradation. Also, a clearly negative correlation between the expression levels of ULK1 and p-MAPK1/3 was observed in human breast cancer tissues. The MAP2K/MEK inhibitor trametinib is sufficient to restore mitophagy function via upregulation of ULK1, leading to inhibition of NLRP3 inflammasome activation, thereby reduces bone metastasis. These results indicate that ULK1 knockout-mediated mitophagy defect promotes breast cancer bone metastasis and provide evidence to explore MAP2K/MEK- MAPK1/3 pathway inhibitors for therapy, especially in cancers displaying low levels of ULK1.Abbreviations: ATG: autophagy-related; Baf A1: bafilomycin A1; BTRC/β-TrCP: beta-transducin repeat containing E3 ubiquitin protein ligase; CHX: cycloheximide; CM: conditioned media; FBXW7/FBW7: F-box and WD repeat domain containing 7; MAPK1: mitogen-activated protein kinase 1; MTDR: MitoTracker Deep Red; mtROS: mitochondrial reactive oxygen species; microCT: micro-computed tomography; mtROS: mitochondrial reactive oxygen species; OCR: oxygen consumption rate; SQSTM1: sequestosome 1; ACP5/TRAP: acid phosphatase, tartrate resistant; ULK1: unc-51 like autophagy activating kinase 1.

MAPK1/3 kinase-dependent ULK1 degradation attenuates mitophagy and promotes breast cancer bone metastasis.

UNC-51-like kinase 1 (ULK1) is well-known to initiate autophagy, and the downregulation of ULK1 has been found in most breast cancer tissues. Thus, the activation of ULK1-modulated autophagy could be a promising strategy for breast cancer therapy. In this study, we found that ULK1 was remarkably downregulated in breast cancer tissue samples by The Cancer Genome Atlas (TCGA) analysis and tissue microarray (TMA) analysis, especially in triple negative breast cancer (TNBC). To design a ULK1 agonist, we integrated in silico screening and chemical synthesis to acquire a series of small molecule candidates. After rounds of kinase and anti-proliferative activity screening, we discovered the small molecule, LYN-1604, to be the best candidate for a ULK1 agonist. Additionally, we identified that three amino acid residues (LYS50, LEU53, and TYR89) were key to the activation site of LYN-1604 and ULK1 by site-directed mutagenesis and biochemical assays. Subsequently, we demonstrated that LYN-1604 could induce cell death, associated with autophagy by the ULK complex (ULK1-mATG13-FIP200-ATG101) in MDA-MB-231 cells. To further explore LYN-1604-induced autophagic mechanisms, we found some potential ULK1 interactors, such as ATF3, RAD21, and caspase3, by performing comparative microarray analysis. Intriguingly, we found that LYN-1604 induced cell death involved in ATF3, RAD21, and caspase3, accompanied by autophagy and apoptosis. Moreover, we demonstrated that LYN-1604 has potential for good therapeutic effects on TNBC by targeting ULK1-modulated cell death in vivo; thus making this ULK1 agonist a novel potential small-molecule drug candidate for future TNBC therapy.

/pdf/discovery-of-a-small-molecule-targeting-ulk1-modulated-cell-2qy71au84i.pdf

Discovery of a small molecule targeting ULK1-modulated cell death of triple negative breast cancer in vitro and in vivo.

Most triple-negative breast cancer (TNBC) patients fail to respond to T cell-mediated immunotherapies. Unfortunately, the molecular determinants are still poorly understood. Breast cancer is the disease genetically linked to a deficiency in autophagy. Here, we show that autophagy defects in TNBC cells inhibit T cell-mediated tumour killing in vitro and in vivo. Mechanistically, we identify Tenascin-C as a candidate for autophagy deficiency-mediated immunosuppression, in which Tenascin-C is Lys63-ubiquitinated by Skp2, particularly at Lys942 and Lys1882, thus promoting its recognition by p62 and leading to its selective autophagic degradation. High Tenascin-C expression is associated with poor prognosis and inversely correlated with LC3B expression and CD8+ T cells in TNBC patients. More importantly, inhibition of Tenascin-C in autophagy-impaired TNBC cells sensitizes T cell-mediated tumour killing and improves antitumour effects of single anti-PD1/PDL1 therapy. Our results provide a potential strategy for targeting TNBC with the combination of Tenascin-C blockade and immune checkpoint inhibitors.

/pdf/autophagy-deficiency-promotes-triple-negative-breast-cancer-60x14bqubk.pdf

Autophagy deficiency promotes triple-negative breast cancer resistance to T cell-mediated cytotoxicity by blocking tenascin-C degradation.

ULK1 plays an important role in autophagy which is widely involved in the development of breast cancer. However, the function and expression of ULK1 in human breast cancer is still scarcely explored. In this study, we showed that the mRNA and protein levels of ULK1 decreased in 10 of 14 (71.4 %) breast cancer tissues, compared with matched normal tissues. Furthermore, immunohistochemical staining of ULK1 was performed on the tissue microarray containing 298 non-metastatic invasive breast primary cancer tissues and 73 matched adjacent noncancerous tissues. 70.1 % breast cancer specimens displayed none to weak staining of ULK1, however, 78.1 % adjacent noncancerous specimens showed moderate to strong staining of ULK1. Statistical analysis revealed that ULK1 expression was negatively correlated with tumor size (r = −0.176, P = 0.002), lymph node status (r = −0.115, P = 0.048), and pathological stage (r = −0.177, P = 0.002). The log-rank test showed that patients with lower level of ULK1 had a significant shorter distant metastasis-free survival time (P = 0.008) and cancer-related survival time (P = 0.008). Multivariate Cox regression analysis found that ULK1 expression was recognized as an independent prognostic factor (P = 0.034). In addition, a significant positive correlation between expression of ULK1 and LC3A (r = 0.401, P < 0.001), and a significant negative correlation between expression of ULK1 and p62 (r = −0.226, P < 0.001) were observed in our breast cancer cohort. These findings suggest that decreased expression of ULK1 is associated with breast cancer progression, together with closely related to decreased autophagic capacity. ULK1 also may be used as a novel prognostic biomarker for breast cancer patients.

/pdf/low-expression-of-ulk1-is-associated-with-operable-breast-2mfk6m2ncc.pdf

Low expression of ULK1 is associated with operable breast cancer progression and is an adverse prognostic marker of survival for patients

Background and objective Hirsutanol A is a novel sesquiterpene compound purified from fungus chondrostereum sp in Sarcophyton tortuosum. Its pharmacologic effect has not been reported yet. This study aimed to investigate cytotoxic effect of Hirsutanol A on hepatocellular carcinoma (HCC) cells and its mechanism. Methods Hep3B cells were treated with different concentrations of Hirsutanol A. Cell proliferation was detected by MTT assay. The protein expression of LC3 was determined by Western blot. The generation of reactive oxygen species (ROS) was monitored by flow cytometry. Results Hirsutanol A significantly inhibited proliferation of Hep3B cells with 50% inhibition concentrations (IC50) of 14.54, 6.71, and 3.59 micromol/L when exposed to Hirsutanol A for 24, 48, and 72 h, respectively. Incubation of Hep3B cells with Hirsutanol A markedly increased the level of ROS and the autophagy marker MAP-LC3 conversion from type I to type II. Pre-incubation with an antioxidant N-acetyl cystein (NAC) decreased the level of ROS, and reduced MAP-LC3 I-II conversion, and suppressed cell death. Blocking autophagy with a specific autophagy inhibitor 3-methyladenine (3-MA), the cytotoxic effect of this compound was attenuated. Conclusion Hirsutanol A has potent cytotoxic effect, and can induce autophagic cell death via increasing ROS production.

A novel sesquiterpene Hirsutanol A induces autophagical cell death in human hepatocellular carcinoma cells by increasing reactive oxygen species.

Background
Topotecan produces DNA damage that induces autophagy in cancer cells. In this study, sensitising topotecan to colon cancer cells with different P53 status via modulation of autophagy was examined.

/pdf/the-inhibition-of-autophagy-sensitises-colon-cancer-cells-5e165lbppu.pdf

The inhibition of autophagy sensitises colon cancer cells with wild-type p53 but not mutant p53 to topotecan treatment.

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Low expression of ULK1 is associated with operable breast cancer progression and is an adverse prognostic marker of survival for patients

A novel sesquiterpene Hirsutanol A induces autophagical cell death in human hepatocellular carcinoma cells by increasing reactive oxygen species.

The inhibition of autophagy sensitises colon cancer cells with wild-type p53 but not mutant p53 to topotecan treatment.