EP4 receptor agonist CAY10598 upregulates ROS-dependent Hsp90 cleavage in colorectal cancer cells.

Prostaglandin E2 (PGE2) interacts with four specific G protein-coupled receptors, namely EP1, EP2, EP3, and EP4, playing a pivotal role in determining the fate of cells. Our previous findings highlighted that stimulating the EP4 receptor with its agonist, CAY10598, triggers apoptosis in colon cancer HCT116 cells via the production of reactive oxygen species (ROS). This process also reduces the phosphorylation of the oncogenic protein JAK2 and leads to its degradation in these cells. In this study, our goal was to explore the pathways through which CAY10598 leads to JAK2 degradation. We focused on Hsp90, a heat shock protein family member known for its role as a molecular chaperone maintaining the stability of several key proteins including EGFR, MET, Akt, and JAK2. Our results show that CAY10598 decreases the levels of client proteins of Hsp90 in HCT116 cells, an effect reversible by pretreatment with the ROS scavenger N-acetyl cysteine (NAC) or the proteasome inhibitor MG132, indicating that the degradation is likely driven by ROS. Furthermore, we observed that CAY10598 cleaves both α and ß isoforms of Hsp90, the process inhibited by NAC. Inhibition of EP4 with the antagonist GW627368x not only prevented the degradation of Hsp90 client proteins but also the cleavage of Hsp90 itself in CAY10598-treated HCT116 cells. Additionally, CAY10598 suppressed the growth of HCT116 cells implanted in mice. Our findings reveal that CAY10598 induces apoptosis in cancer cells by a novel mechanism involving the ROS-dependent cleavage of Hsp90, thereby inhibiting the function of crucial Hsp90 client proteins.

Elucidating the Role of Lipid-Metabolism-Related Signal Transduction and Inhibitors in Skin Cancer.

Lipids, as multifunctional molecules, play a crucial role in a variety of cellular processes. These include regulating membrane glycoprotein functions, controlling membrane trafficking, influencing apoptotic pathways, and affecting drug transport. In addition, lipid metabolites can alter the surrounding microenvironment in ways that might encourage tumor progression. The reprogramming of lipid metabolism is pivotal in promoting tumorigenesis and cancer progression, with tumors often displaying significant changes in lipid profiles. This review concentrates on the essential factors that drive lipid metabolic reprogramming, which contributes to the advancement and drug resistance in melanoma. Moreover, we discuss recent advances and current therapeutic strategies that employ small-molecule inhibitors to target lipid metabolism in skin cancers, particularly those associated with inflammation and melanoma.

Targeting cyclooxygenase-2 for chemoprevention of inflammation-associated intestinal carcinogenesis: An update.

Mounting evidence from preclinical and clinical studies suggests that persistent inflammation functions as a driving force in the journey to cancer. Cyclooxygenase-2 (COX-2) is a key enzyme involved in inflammatory signaling. While being transiently upregulated upon inflammatory stimuli, COX-2 has been found to be consistently overexpressed in human colorectal cancer and several other malignancies. The association between chronic inflammation and cancer has been revisited: cancer can arise when inflammation fails to resolve. Besides its proinflammatory functions, COX-2 also catalyzes the production of pro-resolving as well as anti-inflammatory metabolites from polyunsaturated fatty acids. This may account for the side effects caused by long term use of some COX-2 inhibitory drugs during the cancer chemopreventive trials. This review summarizes the latest findings highlighting the dual functions of COX-2 in the context of its implications in the development, maintenance, and progression of cancer.

YES1 as a potential target to overcome drug resistance in EGFR-deregulated non-small cell lung cancer.

Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) such as gefitinib and osimertinib have primarily been used as first-line treatments for patients with EGFR-activating mutations in non-small cell lung cancer (NSCLC). Novel biomarkers are required to distinguish patients with lung cancer who are resistant to EGFR-TKIs. The aim of the study is to investigate the expression and functional role of YES1, one of the Src-family kinases, in EGFR-TKI-resistant NSCLC. YES1 expression was elevated in gefitinib-resistant HCC827 (HCC827/GR) cells, harboring EGFR mutations. Moreover, HCC827/GR cells exhibited increased reactive oxygen species (ROS) levels compared to those of the parent cells, resulting in the phosphorylation/activation of YES1 due to oxidation of the cysteine residue. HCC827/GR cells showed elevated expression levels of YES1-associated protein 1 (YAP1), NF-E2-related factor 2 (Nrf2), cancer stemness-related markers, and antioxidant proteins compared to those of the parent cells. Knockdown of YES1 in HCC827/GR cells suppressed YAP1 phosphorylation, leading to the inhibition of Bcl-2, Bcl-xL, and Cyclin D1 expression. Silencing YES1 markedly attenuated the proliferation, migration, and tumorigenicity of HCC827/GR cells. Dasatinib inhibited the proliferation of HCC827/GR cells by targeting YES1-mediated signaling pathways. Furthermore, the combination of gefitinib and dasatinib demonstrated a synergistic effect in suppressing the proliferation of HCC827/GR cells. Notably, YES1- and Nrf2-regulated genes showed a positive regulatory relationship in patients with lung cancer and in TKI-resistant NSCLC cell lines. Taken together, these findings suggest that modulation of YES1 expression and activity may be an attractive therapeutic strategy for the treatment of drug-resistant NSCLC.

Emerging Roles of YES1 in Cancer: The Putative Target in Drug Resistance.

Src family kinases (SFKs) are non-receptor tyrosine kinases that are recognized as proto-oncogenic products. Among SFKs, YES1 is frequently amplified and overexpressed in a variety of human tumors, including lung, breast, ovarian, and skin cancers. YES1 plays a pivotal role in promoting cell proliferation, survival, and invasiveness during tumor development. Recent findings indicate that YES1 expression and activation are associated with resistance to chemotherapeutic drugs and tyrosine kinase inhibitors in human malignancies. YES1 undergoes post-translational modifications, such as lipidation and nitrosylation, which can modulate its catalytic activity, subcellular localization, and binding affinity for substrate proteins. Therefore, we investigated the diverse mechanisms governing YES1 activation and its impact on critical intracellular signal transduction pathways. We emphasized the function of YES1 as a potential mechanism contributing to the anticancer drug resistance emergence.

Targeting dysregulated lipid metabolism in the tumor microenvironment.

The reprogramming of lipid metabolism and its association with oncogenic signaling pathways within the tumor microenvironment (TME) have emerged as significant hallmarks of cancer. Lipid metabolism is defined as a complex set of molecular processes including lipid uptake, synthesis, transport, and degradation. The dysregulation of lipid metabolism is affected by enzymes and signaling molecules directly or indirectly involved in the lipid metabolic process. Regulation of lipid metabolizing enzymes has been shown to modulate cancer development and to avoid resistance to anticancer drugs in tumors and the TME. Because of this, understanding the metabolic reprogramming associated with oncogenic progression is important to develop strategies for cancer treatment. Recent advances provide insight into fundamental mechanisms and the connections between altered lipid metabolism and tumorigenesis. In this review, we explore alterations to lipid metabolism and the pivotal factors driving lipid metabolic reprogramming, which exacerbate cancer progression. We also shed light on the latest insights and current therapeutic approaches based on small molecular inhibitors and phytochemicals targeting lipid metabolism for cancer treatment. Further investigations are worthwhile to fully understand the underlying mechanisms and the correlation between altered lipid metabolism and carcinogenesis.

Association of behavior pattern with overweight and obesity in South Korean adults-A multi correspondence analysis (KNHANES-2018-2020).

The objective was to determine the association between health-related behaviour with overweight and obesity in South Korean adults by using the Korean National Health and Nutritional Examination Survey (KNHANES) 2018-2020. The study participants were 16,784 aged ≥ 20years. The variables were socio-demographic, lifestyle, food habits and metabolic conditions. The logistic regression analysis performed to find the association by the odds ratio (OR, 95% CI). MCA performed to identify risk factors were computed for overweight and obesity. Overweight and obesity were significantly associated with health behaviour, high income (OR = 1.26; 95% CI: 1.15-1.39), smoking(OR = 1.29; 95% CI: 1.08-1.53), low physical activity(OR = 3.23; 95% CI: 1.79-4.69), diabetes(OR = 2.70; 95% CI: 1.62-4.50), high cholesterol and low HDL(OR = 3.98; 95%CI:2.65-5.97). The high discriminant variables of MCA were aged over 60years, lower education, high income, diabetes, lack of physical activity, and high cholesterol. The findings confirm that the OR of obesity and overweight was likely associated with health behaviour patterns. Besides, it indicates the MCA would be very effective to identify the population-based data context than individual data and it may suggest that more research on association between health behaviours and obesity prevention interventions should be developed for each age group for better health outcomes.

Factors related to the frequent use of emergency department services in Korea.

BACKGROUND: Frequent Emergency Department (ED) visitors are identified by the policymakers to reduce avoidable ED visits and lessen the financial and operational burden. This study aimed to identify the factors related to the frequent use of ED services. METHODS: This nationwide, cross-sectional observational study was conducted using information obtained from the 2019 National Emergency Department Information System (NEDIS) database. Frequent ED users were defined as patients with four or more ED visits a year. We performed multiple logistic regression analyses to verify the relationship among sociodemographic characteristics, residential characteristics, clinical characteristics, and frequency of ED visits. RESULTS: Among 4,063,640 selected patients, 137,608 patients visited the ED four or more times a year (total number of visits = 735,502 times), which accounted for 3.4% and 12.8% of the total number of ED users and ED visits, respectively. A high ED visit frequency was associated with male sex, age < 9 or ≥ 70 years, Medical Aid (based on the insurance type), lower number of medical institutions and beds compared with that of the national average, and conditions, such as cancer, diabetes, renal failure, and mental illness. A low ED-visit frequency was associated with residence in regions vulnerable to emergency medical care and regions with high income. The possibility of frequent ED visits was high for patients with level 5 severity (non-emergent) and those with an increased need for medical treatment, including older patients and patients with cancer or mental illness. The possibility of frequent ED visits was low for patients aged > 19 years with level 1 severity (resuscitation). CONCLUSIONS: Health service accessibility factors, including low income and medical resource imbalance, were associated with frequent ED visits. Future large-scale prospective cohort studies are warranted to establish an efficient emergency medical system.

Stearoyl-CoA Desaturase 1 as a Therapeutic Biomarker: Focusing on Cancer Stem Cells.

The dysregulation of lipid metabolism and alterations in the ratio of monounsaturated fatty acids (MUFAs) to saturated fatty acids (SFAs) have been implicated in cancer progression and stemness. Stearoyl-CoA desaturase 1 (SCD1), an enzyme involved in lipid desaturation, is crucial in regulating this ratio and has been identified as an important regulator of cancer cell survival and progression. SCD1 converts SFAs into MUFAs and is important for maintaining membrane fluidity, cellular signaling, and gene expression. Many malignancies, including cancer stem cells, have been reported to exhibit high expression of SCD1. Therefore, targeting SCD1 may provide a novel therapeutic strategy for cancer treatment. In addition, the involvement of SCD1 in cancer stem cells has been observed in various types of cancer. Some natural products have the potential to inhibit SCD1 expression/activity, thereby suppressing cancer cell survival and self-renewal activity.

Overactivated NRF2 induces pseudohypoxia in hepatocellular carcinoma by stabilizing HIF-1α.

Hypoxia-inducible factor-1α (HIF-1α) is highly expressed/activated in most hypoxic tumors including hepatocellular carcinoma (HCC). Another key transcription factor, nuclear factor erythroid 2-related factor 2 (NRF2), is also constitutively overactivated in HCC. In an attempt to determine whether HIF-1α and NRF2 could play complementary roles in HCC growth and progression, we investigated the crosstalk between these two transcription factors and underlying molecular mechanisms in cultured HCC cells and experimentally induced hepatocarcinogenesis as well as clinical settings. While silencing of HIF-1α in HepG2 human hepatoma cells did not alter the protein expression of NRF2, NRF2 knockdown markedly reduced the nuclear accumulation of HIF-1α without influencing its mRNA expression. In diethylnitrosamine-induced hepatocarcinogenesis in wild type mice, there was elevated NRF2 expression with concomitant upregulation of HIF-1α. However, this was abolished in Nrf2 knockout mice. NRF2 and HIF-1α co-localized and physically interacted with each other as assessed by in situ proximity ligation and immunoprecipitation assays. In addition, the interaction between NRF2 and HIF-1α as well as their overexpression was found in tumor specimens obtained from HCC patients. In normoxia, HIF-1α undergoes hydroxylation by a specific HIF-prolyl hydroxylase domain protein (PHD), which facilitates ubiquitination and proteasomal degradation of HIF-1α. NRF2 contributes to pseudohypoxia, by directly binding to the oxygen-dependent degradation (ODD) domain of HIF-1α, which hampers the PHD2-mediated hydroxylation, concomitant recruitment of von-Hippel-Lindau and ubiquitination of HIF-1α.

ARD1 stabilizes NRF2 through direct interaction and promotes colon cancer progression.

AIMS: Aberrant overactivation/overexpression of NRF2 is implicated as a driving event in tumor progression, which has been attributed to its mutation or inactivation of the inhibitory protein, KEAP1. However, alternative mechanisms responsible for sustained activation of NRF2 are less understood. MAIN METHODS: Human colon cancer cell lines and tissues obtained from colorectal cancer (CRC) patients were used. To examine the expression levels of ARD1 and NRF2, Western blot and immunofluorescence analyses were performed. To investigate the potential relevance of NRF2 and ARD1 to human CRC, NRF2 and ARD1 were individually silenced in human colon cancer cells (HCT-116) by transfection with their specific small interfering RNA (siRNA). To determine the functional role of ARD1 in NRF2 regulation, in situ proximate ligation, co-immunoprecipitation, nano-LC-ESI MS/MS, and in vitro acetylation assays were performed. KEY FINDINGS: ARD1 knockdown in human colon cancer cell lines significantly reduced the protein levels of NRF2 without affecting its mRNA expression; however, silencing of NRF2 did not alter ARD1 protein expression. In addition, these two proteins were co-localized and physically interacted with each other both in human colon cancer cells (HCT-116) and human colon tumor tissues. Mechanistically, ARD1 overexpression increased the acetylation levels of NRF2. Moreover, an in vitro acetylation assay and mass spectrometric analysis demonstrated that ARD1 could directly acetylate NRF2. Ectopic expression of mutant forms of ARD1 with defective acetyltransferase activity reduced the stability of NRF2. SIGNIFICANCE: In conclusion, ARD1 may potentiate the oncogenic function of NRF2 in human colon cancer by stabilizing this transcription factor.

Tumor Promoting Effects of Sulforaphane on Diethylnitrosamine-Induced Murine Hepatocarcinogenesis.

Nuclear factor erythroid 2-related factor 2 (NRF2) is a key transcription factor involved in protection against initiation of carcinogenesis in normal cells. Notably, recent studies have demonstrated that aberrant activation of NRF2 accelerates the proliferation and progression of cancer cells. The differential effects of NRF2 on multi-stage carcinogenesis have raised a concern about the validity of NRF2 activators for chemoprevention. This prompted us to assess the effects of sulforaphane (SFN), a prototypic NRF2 activating chemopreventive phytochemical, on experimentally induced carcinogenesis. In the present study, SFN was daily injected intraperitoneally (25 mg/kg) for 3 months to male C57BL/6 mice at 6 months after single intraperitoneal administration of a hepatocarcinogen, diethylnitrosamine (DEN). The liver to body weight ratio, tumor growth, and the number and the size of hepatomas measured at 9 months after DEN administration were significantly higher in SFN-treated mice than those in vehicle-treated mice. Moreover, the expression of NRF2, its target protein NAD(P)H:quinone oxidoreductase 1, and the cell proliferation marker, proliferating cell nuclear antigen was further elevated in DEN plus SFN-treated mice. These results suggest that once hepatocarcinogenesis is initiated, SFN may stimulate tumor progression.

Nuclear Localization of Fibroblast Growth Factor Receptor 1 in Breast Cancer Cells Interacting with Cancer Associated Fibroblasts.

Cancer-associated fibroblasts (CAFs) represent a major component of the tumor microenvironment and interplay with cancer cells by secreting cytokines, growth factors and extracellular matrix proteins. When estrogen receptor-negative breast cancer MDA-MB-231 cells were treated with the CAF-conditioned medium (CAF-CM), Akt and STAT3 involved in cell proliferation and survival were activated through phosphorylation. CAFs secrete fibroblast growth factor 2 (FGF2), thereby stimulating breast cancer cell progression. Akt activation induced by CAF-CM in MDA-MB-231 cells was abolished when FGF2-neutralizing antibody was added. Treatment of MDA-MB-231 cells directly with FGF2 enhanced the phosphorylation of Akt and the FGF receptor (FGFR) substrate, FRS2α. These events were abrogated by siRNA-mediated silencing of FGFR1. In a xenograft mouse model, co-injection of MDA-MB-231 cells with activated fibroblasts expressing FGF2 dramatically enhanced activation of Akt. Stable knockdown of FGFR1 blunted Akt phosphorylation in xenograft tumors. MDA-MB-231 cells co-cultured with CAFs or directly stimulated with FGF2 exhibited enhanced nuclear localization of FGFR1. Notably, FGF2 stimulation produced reactive oxygen species (ROS) accumulation in MDA-MB-231 cells, and FGF2-induced nuclear accumulation of FGFR1 was abrogated by the ROS scavenging agent, N-acetylcysteine.

Association Between Hypertension Management Education and Multiple Healthy Behaviors: A Cross-Sectional Study.

PURPOSE: This study aimed to evaluate the association between hypertension management education and the adoption of multiple healthy behaviors. DESIGN: Cross-sectional study. SETTING: Data from the 2019 Community Health Survey in Korea. SUBJECTS: Of the 213,900 participants in the 2019 database, 89,773 (42.0%) were hypertensive and 124,127 (58.0%) were normotensive. MEASURES: Secondary data analysis included a 1:1 computer-assisted personal interview. "Multiple healthy behaviors" included not smoking, not drinking excessively, and walking briskly. "Hypertension management education" referred to information on hypertension management that participants received from clinics, hospitals, and public health centers, outside consultation with a doctor. ANALYSIS: The association between hypertension management education and the adoption of multiple healthy behaviors was evaluated using multiple logistic regression. RESULTS: In total, 89,773 (42.0%) participants were hypertensive. Among 61,589 patients with diagnosed hypertension, only 7,719 (12.5%) received hypertension management education. Participants who received such education were more likely to adopt multiple healthy behaviors (odds ratio [OR] = 1.27, 95% confidence interval [CI]: 1.21-1.34) than their counterparts (OR = 0.91, 95% CI: 0.89-0.93). Participants with undiagnosed hypertension were least likely to adopt multiple healthy behaviors (OR = 0.89, 95% CI: 0.86-0.92). No causal relationships were ascertained because of the cross-sectional study design. CONCLUSIONS: Education can improve the adoption of multiple healthy lifestyles among hypertensive patients. Patients should be encouraged to participate in hypertension management education.

SKI-G-801, an AXL kinase inhibitor, blocks metastasis through inducing anti-tumor immune responses and potentiates anti-PD-1 therapy in mouse cancer models.

OBJECTIVES: AXL-mediated activation of aberrant tyrosine kinase drives various oncogenic processes and facilitates an immunosuppressive microenvironment. We evaluated the anti-tumor and anti-metastatic activities of SKI-G-801, a small-molecule inhibitor of AXL, alone and in combination with anti-PD-1 therapy. METHODS: In vitro pAXL inhibition by SKI-G-801 was performed in both human and mouse cancer cell lines. Immunocompetent mouse models of tumor were established to measure anti-metastatic potential of SKI-G-801. Furthermore, SKI-G-801, anti-PD-1 or their combination was administered as an adjuvant or neoadjuvant in the 4T1 tumor model to assess their potential for clinical application. RESULTS: SKI-G-801 robustly inhibited pAXL expression in various cell lines. SKI-G-801 alone or in combination with anti-PD-1 potently inhibited metastasis in B16F10 melanoma, CT26 colon and 4T1 breast models. SKI-G-801 inhibited the growth of B16F10 and 4T1 tumor-bearing mice but not immune-deficient mice. An antibody depletion assay revealed that CD8+ T cells significantly contributed to SKI-G-801-mediated survival. Anti-PD-1 and combination group were observed the increased CD8+Ki67+ and effector T cells and M1 macrophage and decreased M2 macrophage, and granulocytic myeloid-derived suppressor cell (G-MDSC) compared to the control group. The neoadjuvant combination of SKI-G-801 and anti-PD-1 therapy achieved superior survival benefits by inducing more profound T-cell responses in the 4T1 syngeneic mouse model. CONCLUSION: SKI-G-801 significantly suppressed tumor metastasis and growth by enhancing anti-tumor immune responses. Our results suggest that SKI-G-801 has the potential to overcome anti-PD-1 therapy resistance and allow more patients to benefit from anti-PD-1 therapy.

Novel Macrocyclic Peptidomimetics Targeting the Polo-Box Domain of Polo-Like Kinase 1.

The polo-box domain (PBD) of Plk1 is a promising target for cancer therapeutics. We designed and synthesized novel phosphorylated macrocyclic peptidomimetics targeting PBD based on acyclic phosphopeptide PMQSpTPL. The inhibitory activities of 16e on Plk1-PBD is >30-fold higher than those of PMQSpTPL. Both 16a and 16e possess excellent selectivity for Plk1-PBD over Plk2/3-PBD. Analysis of the cocrystal structure of Plk1-PBD in complex with 16a reveals that the 3-(trifluoromethyl)benzoyl group in 16a interacts with Arg516 through a π-stacking interaction. This π-stacking interaction, which has not been reported previously, provides insight into the design of novel and potent Plk1-PBD inhibitors. Furthermore, 16h, a PEGlyated macrocyclic phosphopeptide derivative, induces Plk1 delocalization and mitotic failure in HeLa cells. Also, the number of phospho-H3-positive cells in a zebrafish embryo increases in proportion to the amount of 16a. Collectively, the novel macrocyclic peptidomimetics should serve as valuable templates for the design of potent and novel Plk1-PBD inhibitors.

The versatile utility of cysteine as a target for cancer treatment.

Owing to its unique nucleophilicity, cysteine is an attractive sulfhydryl-containing proteinogenic amino acid. It is also utilized in various metabolic pathways and redox homeostasis, as it is used for the component of major endogenous antioxidant glutathione and the generation of sulfur-containing biomolecules. In addition, cysteine is the most nucleophilic amino acid of proteins and can react with endogenous or exogenous electrophiles which can result in the formation of covalent bonds, which can alter the cellular states and functions. Moreover, post-translational modifications of cysteines trigger redox signaling and affect the three-dimensional protein structure. Protein phosphorylation mediated by kinases and phosphatases play a key role in cellular signaling that regulates many physiological and pathological processes, and consequently, the modification of cysteine regulates its activities. The modification of cysteine residues in proteins is critically important for the design of novel types of pharmacological agents. Therefore, in cancer metabolism and cancer cell survival, cysteine plays an essential role in redox regulation of cellular status and protein function. This review summarizes the diverse regulatory mechanisms of cysteine bound to or free from proteins in cancer. Furthermore, it can enhance the comprehension of the role of cysteine in tumor biology which can help in the development of novel effective cancer therapies.

Anticancer natural products targeting immune checkpoint protein network.

Normal cells express surface proteins that bind to immune checkpoint proteins on immune cells to turn them off, whereby the immune system does not attack normal healthy cells. Cancer cells can also utilize this same protective mechanism by expressing surface proteins that can interact with checkpoint proteins on immune cells to overcome the immune surveillance. Immunotherapy is making the best use of the body's own immune system to reinforce anti-tumor responses. The most generally used immunotherapy is the control of immune checkpoints including the cytotoxic T lymphocyte-associated molecule 4 (CTLA-4), programmed cell deathreceptor 1 (PD-1), or programmed cell death ligand-1 (PD-L1). In spite of the clinical effectiveness of immune checkpoint inhibitors, the overall response rate still remains low. Therefore, there have been considerable efforts in searching for alternative immune checkpoint proteins that may work as new therapeutic targets for treatment of cancer. Recent studies have identified several additional novel immune checkpoint targets, including lymphocyte activation gene-3, T cell immunoglobulin and mucin-domain containing-3, T cell immunoglobulin and immunoreceptor tyrosine-based inhibition motif domain, V-domain Ig suppressor of T cell activation, B7 homolog 3 protein, B and T cell lymphocyte attenuator, and inducible T cell COStimulator. Natural compounds, especially those present in medicinal or dietary plants, have been investigated for their anti-tumor effects in various in vitro and in vivo models. Some phytochemicals exert anti-tumor activities based on immunoregulatioby blocking interaction between proteins involved in immune checkpoint signal transduction or regulating their expression/activity. Recently, synergistic anti-cancer effects of diverse phytochemicals with anti-PD-1/PD-L1 or anti-CTLA-4 monoclonal antibody drugs have been continuously reported. Considering an increasing attention to noteworthy therapeutic effects of immune checkpoint inhibitors in the cancer therapy, this review focuses on regulatory effects of selected phytochemicals on immune checkpoint protein network and their combinational effectiveness with immune checkpoint inhibitors targeting tumor cells.

JNK-mediated Ser27 phosphorylation and stabilization of SIRT1 promote growth and progression of colon cancer through deacetylation-dependent activation of Snail.

Sirtuin 1 (SIRT1), an NAD+ -dependent histone/protein deacetylase, has multifaceted functions in various biological events such as inflammation, aging, and energy metabolism. The role of SIRT1 in carcinogenesis, however, is still under debate. Recent studies have indicated that aberrant overexpression of SIRT1 is correlated with metastasis and poor prognosis in several types of malignancy, including colorectal cancer. In the present study, we found that both SIRT1 and SIRT1 phosphorylated on serine 27 were coordinately upregulated in colon cancer patients' tissues and human colon cancer cell lines. This prompted us to investigate a role of phospho-SIRT1 in the context of colon cancer progression. A phosphorylation-defective mutant form of SIRT1, in which serine 27 was substituted by alanine (SIRT1-S27A), exhibited lower protein stability compared to that of wild-type SIRT1. Notably, human colon cancer (HCT-116) cells harboring the SIRT1-S27A mutation showed decreased cell proliferation and reduced capability to form xenograft tumor in athymic nude mice, which was accompanied by diminished transcriptional activity of Snail. HCT-116 cells carrying SIRT1-S27A were less capable of deacetylating the Snail protein, with a concomitant decrease in the levels of interleukin (IL)-6 and IL-8 mRNA transcripts. Taken together, these observations suggest that SIRT1 stabilized through phosphorylation on serine 27 exerts oncogenic effects at least partly through deacetylation-dependent activation of Snail and subsequent transcription of IL-6 and IL-8 in human colon cancer cells.

A Structural Approach into Drug Discovery Based on Autophagy.

Autophagy is a lysosome-dependent intracellular degradation machinery that plays an essential role in the regulation of cellular homeostasis. As many studies have revealed that autophagy is related to cancer, neurodegenerative diseases, metabolic diseases, and so on, and it is considered as a promising drug target. Recent advances in structural determination and computational technologies provide important structural information on essential autophagy-related proteins. Combined with high-throughput screening methods, structure-activity relationship studies have led to the discovery of molecules that modulate autophagy. In this review, we summarize the recent structural studies on autophagy-related proteins and the discovery of modulators, indicating that targeting autophagy can be utilized as an effective strategy for novel drug development.