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Endocrine‐resistant ER+HER2– breast cancer (BC) is particularly aggressive and leads to poor clinical outcomes. Effective therapeutic strategies against endocrine‐resistant BC remain elusive. Here, analysis of the RNA‐sequencing data from ER+HER2– BC patients receiving neoadjuvant endocrine therapy and spatial transcriptomics analysis both show the downregulation of innate immune signaling sensing cytosolic DNA, which primarily occurs in endocrine‐resistant BC cells, not immune cells. Indeed, compared with endocrine‐sensitive BC cells, the activity of sensing cytosolic DNA through the cGAS‐STING pathway is attenuated in endocrine‐resistant BC cells. Screening of kinase inhibitor library show that this effect is mainly mediated by hyperactivation of AKT1 kinase, which binds to kinase domain of TBK1, preventing the formation of a trimeric complex TBK1/STING/IRF3. Notably, inactivation of cGAS–STING signaling forms a positive feedback loop with hyperactivated AKT1 to promote endocrine resistance, which is physiologically important and clinically relevant in patients with ER+HER2– BC. Blocking the positive feedback loop using the combination of an AKT1 inhibitor with a STING agonist results in the engagement of innate and adaptive immune signaling and impairs the growth of endocrine‐resistant tumors in humanized mice models, providing a potential strategy for treating patients with endocrine‐resistant BC. [ABSTRACT FROM AUTHOR]

Targeting ferroptosis for cancer therapy has slowed because of an incomplete understanding of ferroptosis mechanisms under specific pathological contexts such as tumorigenesis and cancer treatment. Here, we identify TRPML1-mediated lysosomal exocytosis as a potential anti-ferroptotic process through genome-wide CRISPR-Cas9 activation and kinase inhibitor library screening. AKT directly phosphorylated TRPML1 at Ser343 and inhibited K552 ubiquitination and proteasome degradation of TRPML1, thereby promoting TRPML1 binding to ARL8B to trigger lysosomal exocytosis. This boosted ferroptosis defense of AKT-hyperactivated cancer cells by reducing intracellular ferrous iron and enhancing membrane repair. Correlation analysis and functional analysis revealed that TRPML1-mediated ferroptosis resistance is a previously unrecognized feature of AKT-hyperactivated cancers and is necessary for AKT-driven tumorigenesis and cancer therapeutic resistance. TRPML1 inactivation or blockade of the interaction between TRPML1 and ARL8B inhibited AKT-driven tumorigenesis and cancer therapeutic resistance in vitro and in vivo by promoting ferroptosis. A synthetic peptide targeting TRPML1 inhibited AKT-driven tumorigenesis and enhanced the sensitivity of AKT-hyperactivated tumors to ferroptosis inducers, radiotherapy, and immunotherapy by boosting ferroptosis in vivo. Together, our findings identified TRPML1 as a therapeutic target in AKT-hyperactivated cancer. Editor's summary: Ferroptosis is a nonapoptotic form of regulated cell death and has been an attractive target for cancer therapy; however, the incomplete understanding of its underlying mechanism in tumorigenesis and resistance has limited its use. Here, Zhang et al. have identified transient receptor potential muclipin 1 (TRPML1) as a potential anti-ferroptotic process and target in AKT-driven cancer. They confirmed in vivo that TRPML1 inactivation using a synthetic peptide could increase sensitivity of AKT-hyperactivated tumors to ferroptosis inducers. This highlights TRPML1 as a promising therapeutic target that requires further evaluation. —Dorothy Hallberg [ABSTRACT FROM AUTHOR]

Amino acid-directed strategy becomes an efficient way to explore the alkaloids' biosynthetic potential of marine fungi. The metabolites of marine fungus Monascus albidus BB3 were regulated obviously when cultured in GPY medium supplemented with L-tryptophan, L-phenylalanine, D,L-methionine, L-threonine, L-lysine, L-serine and L-valine. Four new γ-lactams, monascuslactams A–D (1–4), together with two known compounds pulchellalactam (5) and O-acetylperlolyrine (6) were obtained. Their structures were determined by comprehensive analysis on the 1 D and 2 D NMR, HRESIMS, UV and IR data, and their absolute configurations were assigned by the experimental and calculated ECD data analysis. Compounds 3, 4 and 6 showed moderate cytotoxicity against human cancer cell lines SUNE1, HepG2, QGY7701, GLC82, HCT116 and MDA-MB-231. [ABSTRACT FROM AUTHOR]

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 [ABSTRACT FROM AUTHOR]

Aim: Our previous transcriptome sequencing analysis detected that retinol dehydrogenase 16 (RDH16) was dramatically downregulated in hepatocellular carcinoma (HCC). RDH16 belongs to the short‐chain dehydrogenases/reductases super family, and its role in HCC remains unknown. This study aimed to investigate the expression and function of RDH16 in HCC. Methods: The mRNA and protein level of RDH16 in HCC samples were detected by quantitative real‐time polymerase chain reaction and immunohistochemistry analyses, respectively. The role of RDH16 in HCC was determined by in vitro and in vivo functional studies. Results: Downregulation of RDH16 has been detected in approximately 90% of primary HCCs, which was significantly associated with high serum alpha‐fetoprotein level, tumor size, microsatellite formation, thrombus, and poor overall survival of HCC patients. Compared with non‐tumor tissues, higher density of methylation was identified in HCC samples. In addition, RDH16 increases the level of retinoic acid and blocks the de novo synthesis of fatty acid in HCC cells. Functional study shows that ectopic expression of RDH16 in HCC cells suppresses cell growth, clonogenicity, and cell motility. Conclusions: RDH16 might be a prognostic biomarker and intervention point for new therapeutic strategies in HCC. [ABSTRACT FROM AUTHOR]

Impaired macroautophagy/autophagy and high levels of glycolysis are prevalent in liver cancer. However, it remains unknown whether there is a regulatory relationship between autophagy and glycolytic metabolism. In this study, by utilizing cancer cells with basal or impaired autophagic flux, we demonstrated that glycolytic activity is negatively correlated with autophagy level. The autophagic degradation of HK2 (hexokinase 2), a crucial glycolytic enzyme catalyzing the conversion of glucose to glucose-6-phosphate, was found to be involved in the regulation of glycolysis by autophagy. The Lys63-linked ubiquitination of HK2 catalyzed by the E3 ligase TRAF6 was critical for the subsequent recognition of HK2 by the autophagy receptor protein SQSTM1/p62 for the process of selective autophagic degradation. In a tissue microarray of human liver cancer, the combination of high HK2 expression and high SQSTM1 expression was shown to have biological and prognostic significance. Furthermore, 3-BrPA, a pyruvate analog targeting HK2, significantly decreased the growth of autophagy-impaired tumors in vitro and in vivo (p < 0.05). By demonstrating the regulation of glycolysis by autophagy through the TRAF6- and SQSTM1-mediated ubiquitination system, our study may open an avenue for developing a glycolysis-targeting therapeutic intervention for treatment of autophagy-impaired liver cancer. [ABSTRACT FROM AUTHOR]