Role of phloretin as a sensitizer to TRAIL-induced apoptosis in colon cancer.

Phloretin is one of the apple polyphenols with anticancer activities. Since tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) serves important roles in inducing apoptosis, the present study examined the effect of phloretin on TRAIL-induced apoptosis in colon cancer cells. Treatment with both phloretin and TRAIL markedly suppressed the survival of cancer cells from several colon cancer cell lines compared with that of cells treated with either TRAIL or phloretin. Additionally, decreased numbers of colonies were observed following addition of phloretin and TRAIL. Furthermore, TRAIL- and phloretin-treated HT-29-Luc cells exhibited decreased luciferase activity. Increased apoptosis was observed in phloretin- and TRAIL-treated HT-29-Luc colon cancer cells, accompanying elevated levels of cleaved poly(ADP-ribose) polymerase, and caspase-3, -8 and -9. The expression levels of MCL1 apoptosis regulator BCL2 family member (Mcl-1) were decreased following addition of phloretin in colon cancer cells. In addition, overexpression of Mcl-1 in phloretin- and TRAIL-treated HT-29-Luc cells resulted in increased cell survival. Treatment of HT-29-Luc cells with a combination of cycloheximide (CHX) and phloretin led to a more prominent decrease in Mcl-1 expression compared with that in cells treated with CHX alone, while Mcl-1 expression was recovered by treatment with MG132. Binding of ubiquitin with Mcl-1 was verified using immunoprecipitation. Intraperitoneal injection of both TRAIL and phloretin into tumor xenografts was associated with a decreased tumor volume compared with that following injection with either TRAIL or phloretin. Overall, the present results suggest a synergistic effect of phloretin on TRAIL-induced apoptosis in colon cancer cells.

Analysis of Factors Affecting Neutralizing Antibody Production after COVID-19 Vaccination Using Newly Developed Rapid Point-of-Care Test.

(1) Objective: To investigate the factors that affect rates of neutralizing antibody production and duration after vaccination using the newly developed SARS-CoV-2 POCT. (2) Methods: The production of immunoglobulin and neutralizing antibody in clinical subjects who completed various vaccines was analyzed using the POCT, the semi-quantitative was interpreted by measurement application, and the quantified neutralizing antibody titers were using the ELISA. (3) Results: According to the clinical performance analysis of the POCT, the clinical sensitivity and the specificity were 96.8% (90/93) and 97.7% (167/171), respectively, for the S1 RBD IgG antibody. The clinical sensitivity was 92.22% (83/90), and the clinical specificity was 100.00% (174/174) for neutralizing antibodies. Factors influencing antibody production were analyzed using the whole blood of the five types of second-completed vaccinators (N = 736, 20−80 years old). General and neutralizing antibody and showed significant differences in age (p < 0.0001), vaccine type (p < 0.0001), inoculation interval (p < 0.0001), pain score (p < 0.0001), diabetes (p < 0.0001), and hypertension (p = 0.002). The gender (p = 0.021) and chronic fatigue (p = 0.02) did not show the significance. (4) Conclusions: An acquisition of immunoglobulin and neutralizing antibody varies according to vaccine type, age, days after vaccination, pain degree after vaccination, and underlying diseases. The POCT used in this study will be utilized for clinical recommendations such as deciding whether to receive additional vaccines through the immediate rapid determination of neutralizing antibody generation in the clinical site.

Tailored Therapy Based on Molecular Characteristics in Endometrial Cancer.

Management of endometrial cancer, an adenocarcinoma of the endometrium which occupies most uterine corpus neoplasms, including uterine sarcomas, has been more relevant due to its increasing incidence. Extensive research on tumorigenesis molecular mechanisms and molecular characterization across cancers has brought paradigm shifts in the treatment of various malignant tumors. Endometrial cancer treatment has been traditionally guided according to the disease extent or histology types, while recent studies on molecular features have led to the introduction of targeted agents into clinical use, along with conventional chemotherapeutic agents in patients with recurrent or metastatic disease. Considering the proven efficacy and relatively tolerable toxicities of targeted therapies across malignant tumors, improvement of treatment outcomes is also expected in endometrial cancer by adopting an individualized therapy depending on the specific molecular features. Efficacy assessment of new biological agents is still ongoing based on previous preclinical data on endometrial cancer molecular features. Here, endometrial cancer molecular characterization will be reviewed, and then, we will introduce preclinical data, directing the adoption of new biological agents.

Preferences for life-sustaining treatment in Korean adults: a cross-sectional study.

OBJECTIVES: Life-sustaining treatment is any treatment that serves to prolong life without reversing the underlying medical conditions, and includes cardiopulmonary resuscitation, mechanical ventilation, haemodialysis and left ventricular assist devices. This study aimed to investigate the thoughts on life-sustaining treatment of Koreans and to assess the factors associated with deciding to not receive life-sustaining treatment if they develop a terminal disease. DESIGN: Cross-sectional study. SETTING: Guro-gu centre for dementia from 1 May 2018 to 31 December 2019. PARTICIPANTS: In total, 150 individuals participated in this study. OUTCOME MEASURES: The questionnaire consisted of self-report items with some instructions, demographic characteristics, thoughts on life-sustaining treatment and psychosocial scales. The preferences of the participants were investigated on the assumption that they develop terminal cancer. The psychosocial scales included the Generalised Anxiety Disorder-7 (GAD-7), Patient Health Questionnaire-9 (PHQ-9), Connor-Davidson Resilience Scale and Multidimensional Scale of Perceived Social Support (MSPSS). RESULTS: We classified our participants into two groups: individuals who wanted to receive life-sustaining treatment (IRLT) and individuals who wanted to not receive life-sustaining treatment (INLT). There were twice as many participants in the INLT group than there were in the IRLT. In making this decision, the INLT group focused more on physical and mental distress. Additionally, 32.7% of participants responded that terminal status was an optimal time for this decision, but more participants want to decide it earlier. The GAD-7 and PHQ-9 scores were significantly higher in the INLT group than in the IRLT group. However, the INLT group had significantly lower MSPSS family scores. CONCLUSION: Our findings can help assess issues regarding advance directives and life-sustaining treatment, and will be a reference for designing future studies on this issue.

Prognostic implication of systemic inflammatory markers in young patients with resectable colorectal cancer.

PURPOSE: The prognosis of young colorectal cancer (CRC) patients has not fully been addressed. The prognostic significance of systemic inflammatory markers was examined in those patients. METHODS: A total of 965 patients with resectable CRC were divided into young (≤ 50 years, n = 101) and old groups (> 51 years, n = 864). Neutrophil-to-lymphocyte ratio (NLR) > 5, derived NLR (dNLR) > 3, lymphocyte-to-monocyte ratio (LMR) < 2, platelet-to-lymphocyte ratio (PLR) > 150, and prognostic nutritional index (PNI) < 45 were analyzed for prognosis. Overall survival (OS) and progression-free survival (PFS) were compared using the log-rank test. A multivariate analysis was performed using a Cox proportional hazards regression model. RESULTS: In the young group, NLR > 5, LMR < 2, and PNI < 45 were significantly associated with OS with univariate analyses. dNLR > 3 and those markers showed significance for PFS. LMR < 2 was a significant marker for poor PFS (hazard ratio [HR], 5.81; P = 0.020) in the multivariate analysis. In the old group, all inflammatory markers were significantly associated with OS and PFS with univariate analyses. LMR < 2 (HR, 2.66; P = 0.016) and PNI < 45 (HR, 2.14; P = 0.016) were independently associated with OS in multivariate analyses. PLR > 150 (HR, 1.45; P = 0.036) and PNI < 45 (HR, 1.73; P = 0.002) were significant markers for PFS. CONCLUSION: Systemic inflammation might be one of biologic factors that influence on prognosis of young CRC.

Inflammatory markers as prognostic indicators in pancreatic cancer patients who underwent gemcitabine-based palliative chemotherapy.

BACKGROUND/AIMS: Patients with pancreatic cancer (PC) generally have poor clinical outcomes. Early determination of their prognosis is crucial for developing a therapeutic strategy. Recently, various inflammatory markers have been validated as prognostic indicators for many cancers, including PC. However, few studies have evaluated these markers together. Thus, the purpose of this study was to comprehensively evaluate the value of inflammatory markers as prognostic indicators in patients with advanced PC treated with gemcitabine-based chemotherapy as the first line regimen. METHODS: This was a single-center retrospective study evaluating 302 patients with advanced PC who began first line treatment between November 2004 and August 2016. These patients were monitored until June 2017. Survival rates were assessed with univariate and multivariate analyses. Continuous variables were separated using the normal range or ideal cut-off levels determined by receiver operating curve analyses. RESULTS: Among inflammatory markers evaluated, neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), and C-reactive protein (CRP) to albumin ratio (CRP-albumin ratio) were independent predictors of overall survival (hazard ratio, 1.712, 1.345, and 1.454, respectively). Difference in survival rates was significant (p < 0.001) among three groups divided by the number of marker-related risks. CONCLUSION: Baseline inflammatory markers including NLR, PLR, and CRP-albumin ratio are useful in predicting survival rates in patients with PC. Combining these three markers is proven to be valuable.

Credé maneuver to adjust tape tension during trans-obturator tape mid-urethral sling in mixed urinary incontinence.

INTRODUCTION AND HYPOTHESIS: To evaluate the efficacy of intraoperative extrinsic manual bladder compression (Credé maneuver) for trans-obturator tape adjustment during mid-urethral sling surgery in women with stress urinary incontinence and those with mixed urinary incontinence. METHODS: The study included 148 randomly selected women who underwent mid-urethral sling surgery with trans-obturator tape for stress urinary incontinence between January 2016 and May 2017. Subgroup analysis of 66 women with mixed urinary incontinence included 43 patients from the Credé maneuver group and 23 from the non-Credé maneuver group. In the Credé maneuver group, the pattern of urine leakage was determined during the Credé maneuver, and tape tension was adjusted according to the pattern. RESULTS: The cure rate was 86.6% and improved rate was 11.9% in the Credé maneuver patients. The cure rate was 50.6% and improved rate was 38.3% in the non-Credé maneuver patients. The success rate was significantly higher in the Credé than in the non-Credé maneuver group (p = 0.023). In subgroup analysis of patients with mixed urinary incontinence, the cure rate was 81.4% and improved rate was 16.3% in the Credé maneuver group. The cure rate was 43.5% and improved rate was 47.8% in the non-Credé maneuver group. The cure rate was significantly higher in the Credé maneuver group (p = 0.007). CONCLUSIONS: Intraoperative trans-obturator tape adjustment using the Credé maneuver to identify the leaking pattern significantly improved the success rate in women with mixed urinary incontinence, and Credé maneuver-directed adjustment significantly improved the cure rate.

Pulmonary function is implicated in the prognosis of metastatic non-small cell lung cancer but not in extended disease small cell lung cancer.

BACKGROUND: The impacts of pulmonary function in patients with metastatic non-small cell lung cancer (NSCLC) and extended disease stage small cell lung cancer (SCLC-ED) treated with palliative chemotherapy remain to still be determined. METHODS: Results of spirometry performed in 449 patients with either stage IV NSCLC (n=313) or SCLC-ED (n=136) at diagnosis were reviewed retrospectively. Overall survival (OS) was estimated using the Kaplan-Meier method and compared via a log-rank test. Multivariate analysis was performed using a Cox proportional hazards regression model. RESULTS: The presence of chronic obstructive pulmonary disease (COPD) was not a risk factor for OS in either NSCLC or SCLC. However, NSCLC patients with COPD with a forced expiratory volume in one second (FEV1) value of less than 80% predicted were associated with a worse OS in both univariate and multivariate analyses [hazard ratio (HR): 1.43; 95% confidence interval (CI): 1.04-1.97; P=0.03]. Intriguingly, only the OS of NSCLC patients treated with chemotherapeutic agents was affected by the airflow limitation FEV1 value of less than 80% predicted (P=0.02). Patients with an FEV1 value of less than 80% predicted treated with targeted agents were not associated with OS (P=0.24). On the other hand, NSCLC patients with COPD were significantly linked to the occurrence of pulmonary complications during palliative therapy (P=0.01) but not associated with death resulting from pulmonary complications (P=0.22). CONCLUSIONS: Careful attention is required when chemotherapeutic agents are administered to patients with metastatic NSCLC with accompanying COPD with a FEV1 value of less than 80% predicted.

Early venous thromboembolism at the beginning of palliative chemotherapy is a poor prognostic factor in patients with metastatic pancreatic cancer: a retrospective study.

BACKGROUND: This study investigated the prognostic effects of venous thromboembolism (VTE)-related factors in patients with metastatic pancreatic cancer receiving palliative chemotherapy. Predictive factors for VTE were also investigated. METHODS: A total of 216 patients diagnosed with metastatic pancreatic cancer who received gemcitabine-based palliative chemotherapy at our institution were retrospectively evaluated. RESULTS: VTE occurred in 51 (23.6%) patients during treatment and did not affect survival. However, patients who were diagnosed with VTE at the beginning of chemotherapy showed poor prognosis compared with patients diagnosed with VTE during chemotherapy: all patients (hazard ratio [HR] 1.897, p = 0.008); patients diagnosed with VTE (HR = 3.768, p = 0.001). Low serum sodium (Na) (< 135 mmol/L) and high Khorana score (≥3) were strong predictive factors of early VTE (odds ratio [OR] 5.109; 95% confidence interval [95% CI] = 1.010-25.845; p = 0.049 for Khorana score, OR 10.304; 95% CI = 1.036-102.466; p = 0.047) for hyponatremia). CONCLUSIONS: Our study demonstrated that occurrence and detection of VTE in the early period of chemotherapy was the most significant VTE-related prognostic factor in patients with metastatic pancreatic cancer receiving chemotherapy. Prediction using the Khorana score and serum Na levels would be helpful in early diagnosis of VTE.

Overexpression of Romo1 is an unfavorable prognostic biomarker and a predictor of lymphatic metastasis in non-small cell lung cancer patients.

INTRODUCTION: Reactive oxygen species modulator-1 (Romo1) is a protein that modulates levels of reactive oxygen species (ROS) and has been reported to affect cancer cell invasion and proliferation via persistent inflammation. Several studies have demonstrated the clinical application of Romo1 as a prognostic marker in non-small cell lung cancer (NSCLC); however, there have been no studies investigating the mechanism by which Romo1 adversely affects the prognosis of these patients. METHODS: We examined Romo1, ROS, and vascular endothelial growth factor (VEGF) in tumor tissues immunohistochemically. We conducted survival analyses of patients who had curative resection (n=30) in accordance with clinical parameters including levels of Romo1 expression. RESULTS: Romo1 levels were associated with serologic inflammatory markers and high lymphatic metastatic tendencies. Significantly longer disease-free survival (68.7 vs 24.2 months, P=0.031) and overall survival (92.7 vs 51.6 months) were observed in the group with low Romo1 compared with high Romo1. Survival outcomes were also significantly associated with serologic inflammatory markers. Spearman's correlation analyses demonstrated significant positive correlations of Romo1 expression with VEGF-C (P=0.008, R=0.478) and ROS (P=0.016, R=0.436) in tumor samples. CONCLUSION: The current study demonstrates that Romo1 induces lymphatic metastasis of NSCLC by modulating persistent inflammation and oxidative stress (ROS)/VEGF signaling. Lymphatic metastasis associated with elevated Romo1 was shown to be a key reason for unfavorable survival rates.

Correction: Genipin suppresses colorectal cancer cells by inhibiting the Sonic Hedgehog pathway.

[This corrects the article DOI: 10.18632/oncotarget.21882.].

Upregulation of EphB3 in gastric cancer with acquired resistance to a FGFR inhibitor.

Amplification of fibroblast growth factor receptor2 (FGFR2) has been regarded as a druggable target in gastric cancer (GC). Despite known potential of AZD4547, a selective inhibitor of FGFR 1-3, to suppress tumorigenic effects of activated FGFR2, resistance to the targeted agent has been an unresolved issue. This study was performed to elucidate the mechanism of AZD4547 resistance in GC cells. SNU-16 cells were used to establish an AZD4547-resistant GC cell line, SNU-16R. Elevated phosphorylation of EphB3 was confirmed using the Human Phospho-Receptor Tyrosine Kinase Array kit. A tyrosine kinase inhibitor (TKI) of EphB3 was used to investigate the effects of suppressed EphB3 activity in the SNU-16R cell line. SNU-16R cells exhibited upregulated phosphorylation of EphB3. Treatment of SNU-16R cells with the EphB3 TKI resulted in induction of apoptosis, decreased cellular viability, and cell cycle arrest at sub-G1 phase. SNU-16R cells expressed upregulated levels of N-cadherin, vimentin, Snail, matrix metalloproteinase 2 (MMP-2), and MMP-9, and reduced levels of E-cadherin, characteristic of epithelial to mesenchymal transition (EMT). Matrigel invasion assay also demonstrated the increased invasiveness of SNU-16R cells. EphB3 TKI treatment inhibited EMT of SNU-16R cells. Activation of mammalian target of rapamycin (mTOR) through the Ras-ERK1/2 pathway was suggested as the signal transduction mechanism downstream EphB3 by showing enhanced phosphorylation of Raf-1, MEK1/2, ERK1/2, mTOR and its downstream substrates in SNU-16R cells. As expected, EphB3 TKI decreased phosphorylation of these proteins. Our data suggest phosphorylation of mTOR through signaling by EphB3 is a potential mechanism of AZD4547 resistance in GC cells.

Genipin inhibits the invasion and migration of colon cancer cells by the suppression of HIF-1α accumulation and VEGF expression.

Hypoxia-inducible factor-1 (HIF-1) and vascular endothelial growth factor (VEGF) play important roles in cancer progression in various cancer cell lines. Although genipin, a constituent of Gardenia fruit, has been shown to have anti-tumor activity, its role in the suppression of HIF-1 and its downstream target genes is not well understood. We examined the effect of genipin on the intracellular level of HIF-1α and extracellular level of VEGF using the colon cancer cell line HCT116. We observed that genipin suppressed the accumulation of HIF-1α under hypoxia in various cancer cell lines, including HCT116, via the modulation of protein degradation. Genipin also suppressed the expression of VEGF and the invasion of colon cancer cells by blocking the extracellular signal-regulated kinase signaling pathway. Taken together, our results provide new insights into the potential role of genipin in suppressing colon cancer progression.

Treatment experience for incidentally diagnosed asymptomatic prostate tuberculosis in a patient with history of BCG intravesical therapy.

Intravesical BCG therapy after transurethral resection of bladder tumor (TURB) is considered the most effective treatment for prophylaxis against the recurrence of high risk non-muscle invasive bladder cancer, and generally well tolerated and infectious complication are rare. We reported a case of granulomatous prostatitis is a patient who had undergone intravesical BCG therapy due to non-invasive superficial urothelial carcinoma of bladder. This patient was diagnosed by prostate biopsy because of PSA elevation without any other voiding symptoms and abnormal abscess pocket in transrectal ultrasonography.

Current Strategies of Endocrine Therapy in Elderly Patients with Breast Cancer.

Currently, the growing population of the elderly is one of biggest problems in terms of increase in geriatric diseases. Lack of data from large prospective studies on geriatric breast cancer patients often makes it difficult for clinicians to make treatments decisions for them. Because both benefit and risk of treatment should be taken into account, treatment is usually determined considering life expectancy or comorbidities in elderly patients. Treatment of breast cancer is differentiated according to histologic classifications, and hormone therapy is even adopted for patients with metastatic breast cancer if tumor tissue expresses hormone receptors. Endocrine therapy can offer great benefit to elderly patients considering its equivalent efficacy to chemotherapy with fewer toxicities if it is appropriately used. Aromatase inhibitors are usually prescribed agents in hormone therapy for elderly breast cancer patients due to their physiology after menopause. Here, endocrine therapy for elderly patients with breast cancer in neoadjuvant, adjuvant, and palliative setting is reviewed along with predictive adverse events resulting from the use of hormone agents.

Efficacy of second-line treatment and importance of comorbidity scores and clinical parameters affecting prognosis in elderly patients with non-small cell lung cancer without epidermal growth factor receptor mutations.

The present study investigated the importance of comorbidity scores and clinical parameters in elderly patients with non-small cell lung cancer (NSCLC) not harboring epidermal growth factor receptor (EGFR) mutations who received second-line chemotherapy. The present study also compared the efficacy of tyrosine kinase inhibitor and cytotoxic chemotherapy as second-line treatment in elderly patients. The present study retrospectively reviewed the treatment of elderly patients with NSCLC (≥70 years old) who received second-line chemotherapy at Korea University Guro Hospital. Patients who had an EGFR mutation were excluded from the analysis. Between 2005 and 2013, 126 patients were included in the present study. The median progression-free survival (PFS) and overall survival (OS) for all patients who received second-line treatment were 2.47 months [95% confidence interval (CI), 2.08-2.86] and 8.63 months (95% CI, 5.99-11.28), respectively. A total of 52 patients (41.3%) were treated with tyrosine kinase inhibitor (TKI) and 74 (58.7%) were treated with chemotherapy. No difference was observed in the median PFS and OS between the TKI and chemotherapy groups (P=0.287 for PFS and P=0.374 for OS). The Charlson comorbidity index was not associated with survival, whereas a simplified comorbidity score and clinical factors, including poor performance status, short PFS of first-line chemotherapy, presence of brain metastasis and low serum albumin and sodium levels were significant prognostic factors in these elderly patients. Second-line chemotherapy was not beneficial to patients who had at least 3 of these factors and a median OS of 1.73 months, whereas patients who had less than 2 of these factors had a median OS of 11.50 months. For elderly lung cancer patients without EGFR mutations, clinical parameters were the most important factors affecting survival, rather than the types of drugs.

Anatomical distribution and detection rate of colorectal neoplasms according to age in the colonoscopic screening of a Korean population.

PURPOSE: Because data as a basis for the determination of proper age and modality for screening of colorectal neoplasms is lacking, we evaluated detection rates and anatomical distribution of colorectal neoplasms according to age in healthy individuals who underwent total colonoscopy for health checkup. METHODS: A total of 16,100 cases that had received the colonoscopic examination from January to December in 2014 were analyzed. The total number of individuals who received total colonoscopy were divided by the number of individuals harboring colorectal adenoma to calculate the detection rate of colorectal adenoma. Individuals ≤50 years old were classified as young-age group and aged >50 were old-age group. Differences in anatomical locations of colorectal neoplasms were analyzed in the 2 age groups by chi-square test. Risk factors for colorectal adenoma in each age group were analyzed using univariate and multivariate logistic regression analyses. RESULTS: Detection rates of colorectal adenoma were 13.7% in all cases and 12.8% for those in their 40's. The main anatomical location of colorectal adenoma was proximal colon in both age groups (P < 0.001). Hyperplastic polyp was mainly distributed to the distal colon in both age groups (P < 0.001). Distal colon was the major site for colorectal cancer in the old-age group (P = 0.001). Proximal location of neoplasms was a risk factor for colorectal adenoma in both age groups with multivariate analysis. CONCLUSION: These data could be the bases for earlier initiation of screening for colorectal neoplasms with total colonoscopy to detect clinically significant colorectal polyps.

Prognostic significance of interim 18 F-fluorodeoxyglucose positron emission tomography-computed tomography volumetric parameters in metastatic or recurrent gastric cancer.

AIM: To evaluate the prognostic role of interim analysis of 18F-fluorodeoxyglucose (FDG) positron emission tomography-computed tomography (PET/CT) volumetric parameters in patients with recurrent or metastatic advanced gastric cancer (AGC) treated with fluoropyrimidine-based palliative chemotherapy. METHODS: Forty-four patients who underwent baseline and interim PET/CT scanning during palliative chemotherapy were analyzed retrospectively. Initial and change of metabolic parameters (MP) - metabolic tumor volume (MTV), tumor lesion glycolysis (TLG) and maximum and mean standardized uptake values (SUV) were measured with PET/CT. Metabolic change was measured by ∆MP (%)  =  (MPinterim  - MPinitial )/MP initial   ×  100. Independent t-test was employed to compare values of initial, interim and change of metabolic parameters between each response group. Log-rank test was employed for univariate analysis, and multivariate analysis was performed using the Cox proportional hazards regression model to determine independently significant prognostic factors. RESULTS: Reduced percentage values of maximum and mean SUV on interim PET/CT and initial values of volumetric parameters (MTV and TLG) were significant predicting factors to response to fluoropyrimidine-based palliative chemotherapy. The decreased percentage values of metabolic parameters as well as maximum and mean SUV with receiver operating characteristic (ROC) curve determined cut-off points were significant prognostic factors for overall survival and progression-free survival in univariate and multivariate analyses. CONCLUSION: Measurement of metabolic decrease of volumetric parameters by interim PET/CT analysis is useful to determine the prognosis of patients with recurrent or metastatic AGC.

Genipin suppresses colorectal cancer cells by inhibiting the Sonic Hedgehog pathway.

Genipin, a major component of Gardenia jasminoides Ellis fruit, has been shown to inhibit the growth of gastric, prostate, and breast cancers. However, the anti-proliferative activity of genipin in colorectal cancer (CRC) has not been characterized. Herein, we demonstrated that genipin inhibits the proliferation of CRC cells and that genipin suppressed the Hedgehog pathway. Further investigation showed that p53 and NOXA protein levels were increased during inhibition of Hedgehog pathway-mediated apoptosis in CRC cells. We also showed that p53 modulated the expression of NOXA during genipin-induced apoptosis, and suppression via SMO also played a role in this process. Subsequently, GLI1 was ubiquitinated by the E3 ligase PCAF. In a xenograft tumor model, genipin suppressed tumor growth, which was also associated with Hedgehog inactivation. Taken together, these results suggest that genipin induces apoptosis through the Hedgehog signaling pathway by suppressing p53. These findings reveal a novel regulatory mechanism involving Hedgehog/p53/NOXA signaling in the modulation of CRC cell apoptosis and tumor-forming defects.

Cyclopamine sensitizes TRAIL-resistant gastric cancer cells to TRAIL-induced apoptosis via endoplasmic reticulum stress-mediated increase of death receptor 5 and survivin degradation.

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is one of the most effective cancer treatments owing to its ability to selectively kill cancer cells, without affecting normal cells. However, it has been reported that several gastric cancer cells show resistance to TRAIL because of a scarcity of death receptor 5 (DR5) expressed on the cell surface. In this study, we show that cyclopamine sensitizes gastric cancer cells to TRAIL-induced apoptosis by elevating the expression of DR5. Interestingly, survivin hampers the existence of DR5 protein under normal conditions and cyclopamine decreases the expression of survivin, thus acting as a TRAIL sensitizer. Mechanistically, cyclopamine induces endoplasmic reticulum (ER) stress via reactive oxygen species (ROS) and CHOP, the last protein of the ER stress pathway and it regulates the proteasome degradation of survivin. Taken together, our results indicate that cyclopamine can be used for combination therapy in TRAIL-resistant gastric cancer cells.