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The Journal of Experimental Medicine Nov 2023Targeting the PI3K-AKT-mTOR pathway is a promising therapeutic strategy for breast cancer treatment. However, low response rates and development of resistance to...
Targeting the PI3K-AKT-mTOR pathway is a promising therapeutic strategy for breast cancer treatment. However, low response rates and development of resistance to PI3K-AKT-mTOR inhibitors remain major clinical challenges. Here, we show that MYC activation drives resistance to mTOR inhibitors (mTORi) in breast cancer. Multiomic profiling of mouse invasive lobular carcinoma (ILC) tumors revealed recurrent Myc amplifications in tumors that acquired resistance to the mTORi AZD8055. MYC activation was associated with biological processes linked to mTORi response and counteracted mTORi-induced translation inhibition by promoting translation of ribosomal proteins. In vitro and in vivo induction of MYC conferred mTORi resistance in mouse and human breast cancer models. Conversely, AZD8055-resistant ILC cells depended on MYC, as demonstrated by the synergistic effects of mTORi and MYCi combination treatment. Notably, MYC status was significantly associated with poor response to everolimus therapy in metastatic breast cancer patients. Thus, MYC is a clinically relevant driver of mTORi resistance that may stratify breast cancer patients for mTOR-targeted therapies.
Topics: Humans; Animals; Mice; Female; Breast Neoplasms; MTOR Inhibitors; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; TOR Serine-Threonine Kinases
PubMed: 37642941
DOI: 10.1084/jem.20211743 -
Cell Death & Disease Aug 2023Breast cancer (BC) is one of the most frequent cancer-related deaths in women worldwide. Studies have shown the potential impact of circRNAs in multiple human...
Breast cancer (BC) is one of the most frequent cancer-related deaths in women worldwide. Studies have shown the potential impact of circRNAs in multiple human tumorigeneses. Research on the vital signaling pathways and therapeutic targets of circRNAs is indispensable. Here, we aimed to investigate the clinical implications and underlying mechanisms of circ_0042881 in BC. RT-qPCR validated circ_0042881 was notably elevated in BC tissues and plasma, and closely associated with BC clinicopathological features. Functionally, circ_0042881 significantly accelerated the proliferation, migration, and invasion of BC cells in vitro and tumor growth and metastasis in vivo. Mechanistically, circ_0042881 promoted BC progression by sponging miR-217 to relieve its inhibition effect in son of sevenless 1 (SOS1), which further activated RAS protein and initiated downstream signaling cascades, including MEK/ERK pathway and PI3K/AKT pathway. We also demonstrated that treatment of BAY-293, an inhibitor of SOS1 and RAS interaction, attenuated BC progression induced by circ_0042881 overexpression. Furthermore, Eukaryotic initiation factor 4A-III (EIF4A3) could facilitate circ_0042881 circularization. Altogether, we proposed a novel signaling network in which circ_0042881, induced by EIF4A3, influences the process of BC tumorigenesis and metastasis by miR-217/SOS1 axis.
Topics: Female; Humans; Breast Neoplasms; Nuclear Family; Phosphatidylinositol 3-Kinases; RNA, Circular; Carcinogenesis; MicroRNAs; Eukaryotic Initiation Factor-4A; DEAD-box RNA Helicases
PubMed: 37626035
DOI: 10.1038/s41419-023-06085-4 -
ELife Dec 2023Why does protein kinase A respond to purine nucleosides in certain pathogens, but not to the cyclic nucleotides that activate this kinase in most other organisms?
Why does protein kinase A respond to purine nucleosides in certain pathogens, but not to the cyclic nucleotides that activate this kinase in most other organisms?
Topics: Leishmania donovani; Ligands; Phosphotransferases; Cyclic AMP-Dependent Protein Kinases; Purine Nucleosides; Trypanosoma brucei brucei
PubMed: 38126364
DOI: 10.7554/eLife.94720 -
Journal of Enzyme Inhibition and... Dec 2023Phosphoinositide 3-kinases (PI3K) and phosphoinositide 3-kinase-related protein kinases (PIKK) are two structurally related families of kinases that play vital roles in... (Review)
Review
Phosphoinositide 3-kinases (PI3K) and phosphoinositide 3-kinase-related protein kinases (PIKK) are two structurally related families of kinases that play vital roles in cell growth and DNA damage repair. Dysfunction of PIKK members and aberrant stimulation of the PI3K/AKT/mTOR signalling pathway are linked to a plethora of diseases including cancer. In recent decades, numerous inhibitors related to the PI3K/AKT/mTOR signalling have made great strides in cancer treatment, like copanlisib and sirolimus. Notably, most of the PIKK inhibitors (such as VX-970 and M3814) related to DNA damage response have also shown good efficacy in clinical trials. However, these drugs still require a suitable combination therapy to overcome drug resistance or improve antitumor activity. Based on the aforementioned facts, we summarised the efficacy of PIKK, PI3K, and AKT inhibitors in the therapy of human malignancies and the resistance mechanisms of targeted therapy, in order to provide deeper insights into cancer treatment.
Topics: Humans; Phosphatidylinositol 3-Kinase; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Phosphoinositide-3 Kinase Inhibitors; TOR Serine-Threonine Kinases; Neoplasms; Protein Kinase Inhibitors
PubMed: 37489050
DOI: 10.1080/14756366.2023.2237209 -
The Journal of Clinical Investigation Jan 2024Since the discovery that cGAS/STING recognizes endogenous DNA released from dying cancer cells and induces type I interferon and antitumor T cell responses, efforts to... (Review)
Review
Since the discovery that cGAS/STING recognizes endogenous DNA released from dying cancer cells and induces type I interferon and antitumor T cell responses, efforts to understand and therapeutically target the STING pathway in cancer have ensued. Relative to other cancer types, the glioma immune microenvironment harbors few infiltrating T cells, but abundant tumor-associated myeloid cells, possibly explaining disappointing responses to immune checkpoint blockade therapies in cohorts of patients with glioblastoma. Notably, unlike most extracranial tumors, STING expression is absent in the malignant compartment of gliomas, likely due to methylation of the STING promoter. Nonetheless, several preclinical studies suggest that inducing cGAS/STING signaling in the glioma immune microenvironment could be therapeutically beneficial, and cGAS/STING signaling has been shown to mediate inflammatory and antitumor effects of other modalities either in use or being developed for glioblastoma therapy, including radiation, tumor-treating fields, and oncolytic virotherapy. In this Review, we discuss cGAS/STING signaling in gliomas, its implications for glioma immunobiology, compartment-specific roles for STING signaling in influencing immune surveillance, and efforts to target STING signaling - either directly or indirectly - for antiglioma therapy.
Topics: Humans; Glioblastoma; Nucleotidyltransferases; Signal Transduction; Glioma; DNA; Tumor Microenvironment
PubMed: 38226619
DOI: 10.1172/JCI163452 -
Military Medical Research Dec 2023Cell metabolism plays a pivotal role in tumor progression, and targeting cancer metabolism might effectively kill cancer cells. We aimed to investigate the role of...
BACKGROUND
Cell metabolism plays a pivotal role in tumor progression, and targeting cancer metabolism might effectively kill cancer cells. We aimed to investigate the role of hexokinases in prostate cancer (PCa) and identify a crucial target for PCa treatment.
METHODS
The Cancer Genome Atlas (TCGA) database, online tools and clinical samples were used to assess the expression and prognostic role of ADP-dependent glucokinase (ADPGK) in PCa. The effect of ADPGK expression on PCa cell malignant phenotypes was validated in vitro and in vivo. Quantitative proteomics, metabolomics, and extracellular acidification rate (ECAR) and oxygen consumption rate (OCR) tests were performed to evaluate the impact of ADPGK on PCa metabolism. The underlying mechanisms were explored through ADPGK overexpression and knockdown, co-immunoprecipitation (Co-IP), ECAR analysis and cell counting kit-8 (CCK-8) assays.
RESULTS
ADPGK was the only glucokinase that was both upregulated and predicted worse overall survival (OS) in prostate adenocarcinoma (PRAD). Clinical sample analysis demonstrated that ADPGK was markedly upregulated in PCa tissues vs. non-PCa tissues. High ADPGK expression indicates worse survival outcomes, and ADPGK serves as an independent factor of biochemical recurrence. In vitro and in vivo experiments showed that ADPGK overexpression promoted PCa cell proliferation and migration, and ADPGK inhibition suppressed malignant phenotypes. Metabolomics, proteomics, and ECAR and OCR tests revealed that ADPGK significantly accelerated glycolysis in PCa. Mechanistically, ADPGK binds aldolase C (ALDOC) to promote glycolysis via AMP-activated protein kinase (AMPK) phosphorylation. ALDOC was positively correlated with ADPGK, and high ALDOC expression was associated with worse survival outcomes in PCa.
CONCLUSIONS
In summary, ADPGK is a driving factor in PCa progression, and its high expression contributes to a poor prognosis in PCa patients. ADPGK accelerates PCa glycolysis and progression by activating ALDOC-AMPK signaling, suggesting that ADPGK might be an effective target and marker for PCa treatment and prognosis evaluation.
Topics: Humans; Male; Glucokinase; Prostate; AMP-Activated Protein Kinases; Prostatic Neoplasms
PubMed: 38082365
DOI: 10.1186/s40779-023-00500-9 -
Neurobiology of Disease Oct 2023Epilepsy is one of the most common neurological disorders. Neuroinflammation involving the activation of microglia and astrocytes constitutes an important and common...
Epilepsy is one of the most common neurological disorders. Neuroinflammation involving the activation of microglia and astrocytes constitutes an important and common mechanism in epileptogenesis. Transient receptor potential melastatin 2 (TRPM2) is a calcium-permeable, non-selective cation channel that plays pathological roles in various inflammation-related diseases. Our previous study demonstrated that Trpm2 knockout exhibits therapeutic effects on pilocarpine-induced glial activation and neuroinflammation. However, whether TRPM2 in microglia and astrocytes plays a common pathogenic role in this process and the underlying molecular mechanisms remained undetermined. Here, we demonstrate a previously unknown role for microglial TRPM2 in epileptogenesis. Trpm2 knockout in microglia attenuated kainic acid (KA)-induced glial activation, inflammatory cytokines production and hippocampal paroxysmal discharges, whereas Trpm2 knockout in astrocytes exhibited no significant effects. Furthermore, we discovered that these therapeutic effects were mediated by upregulated autophagy via the adenosine monophosphate activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) pathway in microglia. Thus, our findings highlight an important deleterious role of microglial TRPM2 in temporal lobe epilepsy.
Topics: Humans; Microglia; AMP-Activated Protein Kinases; Neuroinflammatory Diseases; TRPM Cation Channels; TOR Serine-Threonine Kinases; Autophagy; Calcium Channels
PubMed: 37648036
DOI: 10.1016/j.nbd.2023.106273 -
Cellular and Molecular Life Sciences :... Sep 2023The receptor interacting protein kinases (RIPK) are a family of serine/threonine kinases that are involved in the integration of various stress signals. In response to... (Review)
Review
The receptor interacting protein kinases (RIPK) are a family of serine/threonine kinases that are involved in the integration of various stress signals. In response to several extracellular and/or intracellular stimuli, RIP kinases engage signaling cascades leading to the activation of NF-κB and mitogen-activated protein kinases, cell death, inflammation, differentiation and Wnt signaling and can have kinase-dependent and kinase-independent functions. Although it was previously suggested that seven RIPKs are part of the RIPK family, phylogenetic analysis indicates that there are only five genuine RIPKs. RIPK1 and RIPK3 are mainly involved in controlling and executing necroptosis in keratinocytes, while RIPK4 controls proliferation and differentiation of keratinocytes and thereby can act as a tumor suppressor in skin. Therefore, in this review we summarize and discuss the functions of RIPKs in skin homeostasis as well as the signaling pathways involved.
Topics: Phylogeny; Skin; Keratinocytes; Mitogen-Activated Protein Kinases; Protein Serine-Threonine Kinases
PubMed: 37688617
DOI: 10.1007/s00018-023-04917-2 -
Clinical and Translational Medicine Jul 2023The stimulator of interferon genes (STING) is an important driver in various inflammatory diseases.
BACKGROUNDS
The stimulator of interferon genes (STING) is an important driver in various inflammatory diseases.
METHODS AND RESULTS
Here, we have demonstrated that inhibition of RIPK3 and MLKL dampens STING signaling, indicating that necroptosis may be involved in sustaining STING signaling. Furthermore, RIPK3 knockout in HT-29 cells significantly suppressed STING signaling. Mechanistically, RIPK3 inhibits autophagic flux during STING activation. RIPK3 knockout inhibits STING signaling by intensifying STING autophagy. In contrast, MLKL regulates the STING pathway bidirectionally. MLKL deficiency enhances STING signaling, whereas suppression of MLKL-mediated pore formation restricts STING signaling. Mechanistically, upon abrogating the pro-necroptotic activity of MLKL, MLKL bound to activated STING is secreted to the extracellular space, where it restricts TBK1 and IRF3 recruitment. Targeting necroptotic signaling ameliorates STING activation during DMXAA-induced intestinal injury and sepsis.
CONCLUSIONS
These findings elucidate molecular mechanisms linking necroptosis to the STING pathway, and suggest a potential benefit of therapeutic targeting of necroptosis in STING-driven inflammatory diseases.
Topics: Humans; Protein Kinases; Autophagy; Sepsis; Receptor-Interacting Protein Serine-Threonine Kinases
PubMed: 37475188
DOI: 10.1002/ctm2.1334 -
Vascular Pharmacology Dec 2023Cardiovascular disease (CVD) is the primary cause of morbidity and mortality in the Western world. Multiple molecular and cellular processes underpinning the... (Review)
Review
Cardiovascular disease (CVD) is the primary cause of morbidity and mortality in the Western world. Multiple molecular and cellular processes underpinning the pathogenesis of CVD are regulated by the zinc finger transcription factor and product of an immediate-early gene, early growth response-1 (Egr-1). Egr-1 regulates multiple pro-inflammatory processes that underpin the manifestation of CVD. The activity of Egr-1 itself is influenced by a range of post-translational modifications including sumoylation, ubiquitination and acetylation. Egr-1 also undergoes phosphorylation by protein kinases, such as extracellular-signal regulated kinase (ERK) which is itself phosphorylated by MEK. This article reviews recent progress on the MEK-ERK-Egr-1 cascade, notably regulation in conjunction with factors and agents such as TET2, TRIB2, MIAT, SphK1, cAMP, teneligliptin, cholinergic drugs, red wine and flavonoids, wogonin, febuxostat, docosahexaenoic acid and AT1R blockade. Such insights should provide new opportunity for therapeutic intervention in CVD.
Topics: Humans; Extracellular Signal-Regulated MAP Kinases; Cardiovascular Diseases; Transcription Factors; Phosphorylation; Mitogen-Activated Protein Kinase Kinases; Calcium-Calmodulin-Dependent Protein Kinases
PubMed: 37734428
DOI: 10.1016/j.vph.2023.107232