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Tumor microenvironment (TME) composes of multiple cell types and non-cellular components, which supports the proliferation, metastasis and immune surveillance evasion of tumor cells, as well as accounts for the resistance to therapies. Therefore, therapeutic strategies using small molecule inhibitors (SMIs) and antibodies to block potential targets in TME are practical for cancer treatment. Targeted protein degradation using PROteolysis-TArgeting Chimera (PROTAC) technic has several advantages over traditional SMIs and antibodies, including overcoming drug resistance. Thus many PROTACs are currently under development for cancer treatment. In this review, we summarize the recent progress of PROTAC development that target TME pathways and propose the potential direction of future PROTAC technique to advance as novel cancer treatment options. [ABSTRACT FROM AUTHOR]

Tumor microenvironment (TME) composes of multiple cell types and non-cellular components, which supports the proliferation, metastasis and immune surveillance evasion of tumor cells, as well as accounts for the resistance to therapies. Therefore, therapeutic strategies using small molecule inhibitors (SMIs) and antibodies to block potential targets in TME are practical for cancer treatment. Targeted protein degradation using PROteolysis-TArgeting Chimera (PROTAC) technic has several advantages over traditional SMIs and antibodies, including overcoming drug resistance. Thus many PROTACs are currently under development for cancer treatment. In this review, we summarize the recent progress of PROTAC development that target TME pathways and propose the potential direction of future PROTAC technique to advance as novel cancer treatment options. [ABSTRACT FROM AUTHOR]

Mitochondrion is the powerhouse of the cell. The research of nearly a century has expanded our understanding of mitochondrion, far beyond the view that mitochondrion is an important energy generator of cells. During the initiation, growth and survival of tumor cells, significant mitochondrial metabolic changes have taken place in the important enzymes of respiratory chain and tricarboxylic acid cycle, mitochondrial biogenesis and dynamics, oxidative stress regulation and molecular signaling. Therefore, mitochondrial metabolic proteins are the key mediators of tumorigenesis. Post-translational modification is the molecular switch that regulates protein function. Understanding how these mitochondria-related post-translational modification function during tumorigenesis will bring new ideas for the next generation of cancer treatment. [Display omitted] • Mitochondrial metabolic proteins are the key mediators of tumorigenesis. • The role of mitochondria in cancer is closely driven by the post-translational modifications (PTMs). • PTMs of mitochondrial metabolic proteins may bring new ideas for cancer treatment. [ABSTRACT FROM AUTHOR]

Aberrancy in cell cycle progression is one of the fundamental mechanisms underlying tumorigenesis, making regulators of the cell cycle machinery rational anticancer therapeutic targets. A growing body of evidence indicates that the cell cycle regulatory pathway integrates into other hallmarks of cancer, including metabolism remodeling and immune escape. Thus, therapies against cell cycle machinery components can not only repress the division of cancer cells, but also reverse cancer metabolism and restore cancer immune surveillance. Besides the ongoing effects on the development of small molecule inhibitors (SMIs) of the cell cycle machinery, proteolysis targeting chimeras (PROTACs) have recently been used to target these oncogenic proteins related to cell cycle progression. Here, we discuss the rationale of cell cycle targeting therapies, particularly PROTACs, to more efficiently retard tumorigenesis. The cell cycle machinery regulates cancer metabolism primarily at the post-translational level, either through phosphorylation of metabolic enzymes or upstream regulators by CDKs or through ubiquitination of these proteins by APC/C or SCF E3 ligases. CDK inhibitors restore cancer immune surveillance, in part by triggering tumor antigen presentation or stimulating the infiltration of immune cells into the tumor, thus providing synergetic effects with immune checkpoint blockade (ICB). Proteolysis targeting chimeras (PROTACs) provide a new cancer therapeutic approach to target cell cycle machinery components with oncogenic roles for proteasomal degradation, which has advantages over traditional small molecular inhibitors (SIMs) in many aspects including distinguishing the protein target from close family members, overcoming potential drug resistance, and repressing the kinase-independent function of protein targets. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is considered a multifactorial disease that affects the central nervous system and periphery. A decline in brain glucose metabolism is an early feature of AD and is accompanied by a phenotypic shift from aerobic glycolysis to ketogenesis. The liver is responsible for the generation of the ketone body. However, the mechanism that underlies hepatic ketogenesis in AD remains unclear. Here, we investigated hepatic ketogenesis during the early stage of AD pathogenesis in amyloid precursor protein (APP SWE ) and presenilin (PSEN1dE9) (APP/PS1) mice. We observed that β-hydroxybutyric acid was increased in the brain of the postmortem mild cognitive impairment and AD subjects and in 3-month-old APP/PS1 AD mice. A rise in 3-hydroxy-3-methylglutary-CoA synthase 2 (HMGCS2), a key enzyme for catalyzing β-hydroxybutyric acid production, was observed in early AD mice. We further showed that proinflammatory cytokines were activated in the liver prior to their activation in the brain of 3-month-old APP/PS1 mice. Among the cytokines, interleukin-6 significantly activated HMGCS2 through the binding of nuclear factor κB (NF-κB) p65 to the HMGCS2 promoter. Additionally, interleukin-6 stimulated phosphorylation of p38 mitogen activated protein kinases, an upstream molecule for NF-κB p65 signaling. We have demonstrated that a hepatic inflammatory factor enhances ketogenesis through HMGCS2 signaling activation by p38/NF-κB p65. These results provide a novel peripheral metabolic mechanism for enhanced ketone production and suggest a plausible early AD phenotype to diagnose AD. [ABSTRACT FROM AUTHOR]