Caffeic Acid Enhances Anticancer Drug-induced Apoptosis in Acid-adapted HCT116 Colon Cancer Cells.

BACKGROUND/AIM: Apoptosis resistance in cancer cells adapted to acidic microenvironments poses a challenge for effective treatment. This study investigated the potential use of caffeic acid as an adjunct therapy to overcome drug resistance in colorectal cancer cells under acidic conditions. MATERIALS AND METHODS: Long-term exposure to low-pH conditions induced resistance in HCT116 colorectal cancer cells. The effects of caffeic acid on proliferation, clonogenicity, and apoptosis induction were assessed alone and in combination with oxaliplatin and 5-Fluorouracil. The signaling pathways involved in drug resistance were examined by assessing the activities of PI3K/Akt and ERK1/2. RESULTS: Caffeic acid inhibited the proliferation and clonogenicity of acid-adapted cancer cells, and enhanced apoptosis when combined with anticancer drugs. Mechanistically, caffeic acid attenuated the hyperactivation of the PI3K/Akt and ERK1/2 signaling pathways associated with drug resistance. CONCLUSION: Caffeic acid is a promising therapeutic agent for targeting resistant cancer cells in acidic microenvironments. Its ability to inhibit proliferation, sensitize cells to apoptosis, and modulate signaling pathways highlights its potential for overcoming drug resistance in cancer therapy.

Intraosseous hemangioma with aneurysmal bone cyst-like changes of the hyoid bone: Case report and literature review.

RATIONALE: Intraosseous hemangioma is a rare benign vascular tumor of the bone that can affect any body part; however, the most common site is the vertebra, followed by calvarial bones. PATIENT CONCERNS: We present a case of intraosseous hemangioma in a 23-year-old male who presented a feeling of fullness in the throat for 3 months. The hyoid bone level had a hard mass of about 5 cm. Fine needle aspiration showed 5 mL dark bloody aspirates. Magnetic resonance image showed a 5.3 cm mixed signal intensity lesion in the hyoid body. DIAGNOSIS: Histopathologic examination showed intraosseous hemangioma with aneurysmal bone cyst (ABC)-like changes in the hyoid bone. INTERVENTIONS: The mass was completely removed without significant problems. OUTCOMES: Complete mass excision and symptomatic improvements were achieved, and no subsequent relapses were observed. LESSONS: The authors experienced a case of intraosseous hemangioma with ABC-like changes. There has been no case report of intraosseous hemangioma in the hyoid bone. This case showed a spectral pattern of the ABC-like changes developing from the underlying bone tumor as a secondary change. ABC-like changes in bone tumors can mislead the diagnosis. Careful examination of the tumor is essential for the correct diagnosis of ABC or ABC-like changes.

Anticancer Effect of Gallic Acid on Acidity-Induced Invasion of MCF7 Breast Cancer Cells.

The acidic tumor environment has emerged as a crucial factor influencing the metastatic potential of cancer. We investigated the effect of an acidic environment on the acquisition of metastatic properties in MCF7 breast cancer cells and explored the inhibitory effects of gallic acid. Prolonged exposure to acidic culture conditions (over 12 weeks at pH 6.4) induced the acquisition of migratory and invasive properties in MCF7 cells, accompanied by increased expression of Matrix Metalloproteinase 2 and 9 (MMP2 and MMP9, respectively), together with alterations in E-cadherin, vimentin, and epithelial-to-mesenchymal transition markers. Gallic acid effectively inhibited the survival of acidity-adapted MCF7 (MCF7-6.4/12w) cells at high concentrations (>30 µM) and reduced metastatic characteristics induced by acidic conditions at low concentration ranges (5-20 µM). Moreover, gallic acid suppressed the PI3K/Akt pathway and the nuclear accumulation of ß-catenin, which were elevated in MCF7-6.4/12w cells. These findings highlight the potential of gallic acid as a promising therapeutic agent for metastatic traits in breast cancer cells under acidic conditions.

Molecular Basis of Resveratrol-Induced Resensitization of Acquired Drug-Resistant Cancer Cells.

Multidrug resistance (MDR) to anticancer drugs remains a serious obstacle to the success of cancer chemotherapy. Resveratrol, a polyphenol, present in natural products exerts anticancer activity and acts as a potential MDR inhibitor in various drug-resistant cancer cells. In the process of resensitization of drug-resistant cancer cells, resveratrol has been shown to interfere with ABC transporters and drug-metabolizing enzymes, increase DNA damage, inhibit cell cycle progression, and induce apoptosis and autophagy, as well as prevent the induction of epithelial to mesenchymal transition (EMT) and cancer stem cells (CSCs). This review summarizes the mechanisms by which resveratrol counteracts MDR in acquired drug-resistant cancer cell lines and provides a critical basis for understanding the regulation of MDR as well as the development of MDR-inhibiting drugs.

Intra-muscular follicular dendritic cell sarcoma in the thigh: A case report.

RATIONALE: Follicular dendritic cell sarcoma (FDCS) is an intermediate-grade malignancy originating from follicular dendritic cells. Nodal FDCS is the most common type, meaning that the extranodal type may not be recognized and could be easily misdiagnosed. Reported extranodal sites include the head and neck, retroperitoneum, spleen, liver, and gastrointestinal tract. FDCS in the soft tissue is extremely rare. PATIENT CONCERNS: A 75-year-old male presented with complaints of a localized swelling and intra-muscular soft tissue mass in the left upper thigh. DIAGNOSIS: The present tumor consisted of fascicular or vague storiform-arranged spindle cells with less pleomorphism and many lymphoid aggregates. Tumor cells were positive for CD21, CD35, CD68, vimentin, and EGFR. Intra-muscular FDCS was confirmed by immunohistochemical studies. INTERVENTIONS: The patient received a wide marginal excision, followed by adjuvant radiotherapy. OUTCOMES: Symptomatic improvements were achieved and no subsequent relapses were observed. LESSONS: If the tumor arises in the extranodal sites, especially in the soft tissue, it is difficult to include FDCS in the differential diagnosis. When the immunoprofile is not consistent with that of common spindle cell tumors, immunostaining for follicular dendritic cell markers such as CD21, CD23, and CD35, as well as further immunohistochemistry for D2-40, CD68, EGFR, Epstein-Barr virus, and BRAF can be helpful for the diagnosis and subtyping of FDCS. To the best of our knowledge, the present case is the first case of intramuscular FDCS.

Cryptococcal infection presenting as soft tissue abscess and arthritis: Case report.

RATIONALE: Cryptococcal infection has been documented in immunocompromised patients. AIDS and renal transplant recipients account for majority of the cases. Most cases present with central nervous system or disseminated disease, with only few presenting soft tissue, bone, and joint manifestations. PATIENT CONCERNS: We present a case of soft tissue mass in a 66-year-old female renal transplant recipient and that of arthritis in a 64-year-old immunocompetent man who presented pseudogout arthropathy. Chest radiographies of both cases were negative. Biopsy revealed cryptococcal organisms. Blood culture or cerebrospinal fluid sampling indicated positive results for cryptococcal antigen. DIAGNOSIS: Cryptococcus neoformans was recovered in the wound culture. INTERVENTIONS: The patients received intravenous fluconazole and flucytosine, followed by oral fluconazole administration. OUTCOMES: Symptomatic improvements were achieved and no subsequent relapses were observed. LESSONS: The authors experienced 2 cases of cryptococcosis with very unusual clinical presentation. Early clinical suspicion and serum cryptococcal antigen testing can help in rapid appropriate diagnosis in immunocompetent as well as immunocompromised patients even in the absence of pulmonary involvement.

Rare Case of Renal-type Clear Cell Carcinoma of the Prostate and Review of the Literature.

BACKGROUND/AIM: Renal-type clear cell carcinoma (RTCCC) occurring as a primary tumor in an extra-renal location, especially in the prostate, is very rare. In this report, we present a rare case of RTCCC of the prostate and review the current literature on this condition. CASE REPORT: The patient was a 76-year-old man who presented with urinary symptoms. Cystoscopic findings showed tumor-like lesions in the dome, neck, and anterior wall of the urinary bladder. Biopsy revealed clear cell carcinoma (CCC). Transrectal needle biopsy of the prostate revealed prostatic adenocarcinoma with CCC features. Immunohistochemically, tumor cells of the bladder and prostate were compatible with prostatic carcinoma. The whole-body radiologic workup did not reveal any renal or other organ malignancies. Transurethral resection of the prostate and bladder tumor was performed. The patient underwent regular follow-up cystoscopic examination and urine cytology. No recurrence was observed 19 months after the diagnosis. CONCLUSION: This was a case of RTCCC arising in the prostate. RTCCC of the prostate is extremely rare and shows very similar histological and immunohistochemical features to those of CCC occurring in the kidney. Pathologists should be aware of such an entity whenever they see clear cells in urinary tract malignancies.

Role of Death Receptors-associated Lipid Rafts in Oxaliplatin-induced Death Mode Regulation of HepG2 Cells.

BACKGROUND/AIM: We previously showed that oxaliplatin induces necrotic-like cell death in hepatocarcinomas, and combination with ursodexoycholic acid (UDCA) significantly shifts the necrotic-like death to apoptosis. Since cell death mode is crucial on inflammatory responses and chemotherapeutic efficacy, the mechanism underlying determination of cell death mode by UDCA was investigated in this study. MATERIALS AND METHODS: Apoptosis or necrosis was determined by apoptotic body formation, caspase-8 activity, LDH release and PI inclusion. The involvement of lipid rafts and death receptors was examined by rafts fractionation, confocal microscopy and gene silencing assays. RESULTS: UDCA combination enhanced recruitment of death receptors and adaptors into cholesterol-enriched lipid rafts, and induced a stronger raft clustering. Lipid raft disruption decreased the UDCA/oxaliplatin-mediated apoptosis and increased necrotic-like death. CONCLUSION: UDCA promotes lipid raft localization of multiple death receptors, thereby contributing to a shift of cell death mode from oxaliplatin-induced necrotic death to apoptosis in HepG2 cells.

Expression and Prognostic Significance of CDK8 and ß-Catenin in Hepatocellular Carcinoma.

BACKGROUND/AIM: Cyclin-dependent kinase 8 (CDK8) is known to play an important role in the early development and progression of various cancers, and the Wnt/ß-catenin pathway is also involved in cancer progression. Nevertheless, relatively little is known about the regulatory mechanisms of the ß-catenin pathway in hepatocellular carcinoma (HCC). MATERIALS AND METHODS: The complete clinicopathological features of 122 pairs of HCC and adjacent non-tumor tissues were analyzed and immunohistochemistry was used to detect the aberrant expression of CDK8 and ß-catenin. Overall survival rates (OSRs) were evaluated using the Kaplan-Meier method and Cox multivariate analysis was used to assess the prognostic values. RESULTS: Aberrant expression of nuclear ß-catenin and CDK8 are independent prognostic variables that negatively affect the OSR. The aberrant expression of CDK8 was associated with the dysregulated expression of ß-catenin and correlated with a poor prognosis. CONCLUSION: Inhibition of CDK8 and/or nuclear ß-catenin expression pattern could serve as a promising therapeutic strategy for the treatment of HCC.

Extracellular acidity­induced expression of Kallikrein­related peptidases 7 and 8 is involved in increased invasiveness of gastric cancer cells.

In several cancers, the acidic microenvironment of cancer cells has been implicated in enhanced malignancy and metastasis. In the present study, it was observed that gastric cancer cell lines, SNU601 and AGS, exposed to an acidic medium had increased invasiveness, as assessed using Matrigel­coated Transwell analysis. The factors regulating such acidity­mediated enhancement of invasiveness were investigated and it was revealed that a low­pH environment markedly increased kallikrein­related peptidase 7 (KLK7) and kallikrein­related peptidase 8 (KLK8) expression. Gene silencing assays confirmed that these peptidases were involved in acidity­promoted invasion. Acidic conditions also increased the expression of cyclooxygenases (COX), key regulatory enzymes in the catalytic pathway of prostaglandin production. Notably, these enzymes appeared to be involved in the acidity­mediated expression of KLK7 and KLK8, as revealed using COX inhibitors. Therefore, it was indicated that tumor invasion enhancement by extracellular acidity is regulated at least in part through the induction of the COX/KLK7 and KLK8 axis in gastric cancer cells.

Ellagic Acid Inhibits Extracellular Acidity-Induced Invasiveness and Expression of COX1, COX2, Snail, Twist 1, and c-myc in Gastric Carcinoma Cells.

Extracellular acidity has been implicated in enhanced malignancy and metastatic features in various cancer cells. Gastric cancer cell lines (AGS and SNU601) maintained in an acidic medium have increased motility and invasiveness. In this study, we investigated the effect of ellagic acid, a plant-derived phenolic compound, on the acidity-promoted migration and invasion of gastric cancer cells. Treating cells maintained in acidic medium with ellagic acid inhibited acidity-mediated migration and invasion, and reduced the expression of MMP7 and MMP9. Examining regulatory factors contributing to the acidity-mediated invasiveness, we found that an acidic pH increased the expression of COX1 and COX2; importantly, expression decreased under the ellagic acid treatment. The general COX inhibitor, sulindac, also decreased acidity-mediated invasion and expression of MMP7 and MMP9. In addition, acidity increased the mRNA protein expression of transcription factors snail, twist1, and c-myc; these were also reduced by ellagic acid. Together, these results suggest that ellagic acid suppresses acidity-enhanced migration and invasion of gastric cancer cells via inhibition of the expression of multiple factors (COX1, COX2, snail, twist1, and c-myc); for this reason, it may be an effective agent for cancer treatment under acidosis.

Reactive oxygen species induce epithelial­mesenchymal transition, glycolytic switch, and mitochondrial repression through the Dlx­2/Snail signaling pathways in MCF­7 cells.

Reactive oxygen species (ROS) are important cellular second messengers involved in various aspects of cell signaling. ROS are elevated in multiple types of cancer cells, and this elevation is known to be involved in pathological processes of cancer. Although high levels of ROS exert cytotoxic effects on cancer cells, low levels of ROS stimulate cell proliferation and survival by inducing several pro­survival signaling pathways. In addition, ROS have been shown to induce epithelial­mesenchymal transition (EMT), which is essential for the initiation of metastasis. However, the precise mechanism of ROS­induced EMT remains to be elucidated. In the present study, it was indicated that ROS induce EMT by activating Snail expression, which then represses E­cadherin expression in MCF­7 cells. It was further indicated that distal­less homeobox­2 (Dlx­2), one of the human Dlx gene family proteins involved in embryonic development, acts as an upstream regulator of ROS­induced Snail expression. It was also revealed that ROS treatment induces the glycolytic switch, a phenomenon whereby cancer cells primarily rely on glycolysis instead of mitochondrial oxidative phosphorylation for ATP production, even in the presence of oxygen. In addition, ROS inhibited oxidative phosphorylation and caused cytochrome c oxidase inhibition via the Dlx­2/Snail cascade. These results suggest that ROS induce EMT, the glycolytic switch and mitochondrial repression by activating the Dlx­2/Snail axis, thereby playing crucial roles in MCF­7 cancer cell progression.

Keratin 6, induced by chronic cisplatin exposure, confers chemoresistance in human gastric carcinoma cells.

Currently, various types of keratins have been reported to be highly expressed in cancer cells and to be associated with a malignant phenotype. In the present study, it was found that expression levels of keratin 6 (K6), keratin 16 (K16), and keratin 17 (K17) were highly elevated in SNU601 cells resistant to cisplatin (SNU601­cis2 and SNU601­cis10), but not in the parental SNU601 cells as confirmed by quantitative PCR, immunoblotting, and immunofluorescence assays. K6 is a type II keratin and is known to form a keratin filament in conjugation with type I keratin, K16 or K17. Thus, we attempted to understand the role of the overexpression of K6/K16 or K6/K17 keratin filaments by regulating the expression of K6. Silencing of K6 by siRNA in SNU601­cis2 cells promoted oxaliplatin­induced apoptosis in the resistant cells as shown by increased apoptotic body formation, caspase­8 and caspase­3 cleavage, and cytochrome c release. In addition, induction of K6 levels in wild­type SNU601 cells, by transfection with pCMV6­K6A and pCMV6­K6B overexpression vectors, resulted in decreased apoptosis in response to cisplatin and L­OHP. Platinum drugs, such as oxaliplatin, were shown to induce the extrinsic apoptotic pathway by inducing lipid raft formation and death receptor recruitment into lipid rafts. However, in the resistant cells, the oxaliplatin­triggered extrinsic apoptotic pathway appeared to be suppressed by decreased lipid raft formation, and recruitment of death receptor 5 and FADD into lipid rafts. Therefore, the increase in the levels of the K6 filament may be associated with the regulation of lipid raft formation and may contribute, at least in part, to resistance to anticancer drugs.

Extracellular acidity enhances tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis via DR5 in gastric cancer cells.

The tumor microenvironment greatly influences cancer cell characteristics, and acidic extracellular pH has been implicated as an essential factor in tumor malignancy and the induction of drug resistance. Here, we examined the characteristics of gastric carcinoma (GC) cells under conditions of extracellular acidity and attempted to identify a means of enhancing treatment efficacy. Acidic conditions caused several changes in GC cells adversely affecting chemotherapeutic treatment. Extracellular acidity did inhibit GC cell growth by inducing cell cycle arrest, but did not induce cell death at pH values down to 6.2, which was consistent with down-regulated cyclin D1 and up-regulated p21 mRNA expression. Additionally, an acidic environment altered the expression of atg5, HSPA1B, collagen XIII, collagen XXAI, slug, snail, and zeb1 genes which are related to regulation of cell resistance to cytotoxicity and malignancy, and as expected, resulted in increased resistance of cells to multiple chemotherapeutic drugs including etoposide, doxorubicin, daunorubicin, cisplatin, oxaliplatin and 5-FU. Interestingly, however, acidic environment dramatically sensitized GC cells to apoptosis induced by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Consistently, the acidity at pH 6.5 increased mRNA levels of DR4 and DR5 genes, and also elevated protein expression of both death receptors as detected by immunoblotting. Gene silencing analysis showed that of these two receptors, the major role in this effect was played by DR5. Therefore, these results suggest that extracellular acidity can sensitize TRAIL-mediated apoptosis at least partially via DR5 in GCs while it confers resistance to various type of chemotherapeutic drugs.

Regulation of Tumor Progression by Programmed Necrosis.

Rapidly growing malignant tumors frequently encounter hypoxia and nutrient (e.g., glucose) deprivation, which occurs because of insufficient blood supply. This results in necrotic cell death in the core region of solid tumors. Necrotic cells release their cellular cytoplasmic contents into the extracellular space, such as high mobility group box 1 (HMGB1), which is a nonhistone nuclear protein, but acts as a proinflammatory and tumor-promoting cytokine when released by necrotic cells. These released molecules recruit immune and inflammatory cells, which exert tumor-promoting activity by inducing angiogenesis, proliferation, and invasion. Development of a necrotic core in cancer patients is also associated with poor prognosis. Conventionally, necrosis has been thought of as an unregulated process, unlike programmed cell death processes like apoptosis and autophagy. Recently, necrosis has been recognized as a programmed cell death, encompassing processes such as oncosis, necroptosis, and others. Metabolic stress-induced necrosis and its regulatory mechanisms have been poorly investigated until recently. Snail and Dlx-2, EMT-inducing transcription factors, are responsible for metabolic stress-induced necrosis in tumors. Snail and Dlx-2 contribute to tumor progression by promoting necrosis and inducing EMT and oncogenic metabolism. Oncogenic metabolism has been shown to play a role(s) in initiating necrosis. Here, we discuss the molecular mechanisms underlying metabolic stress-induced programmed necrosis that promote tumor progression and aggressiveness.

Oncogenic Metabolism Acts as a Prerequisite Step for Induction of Cancer Metastasis and Cancer Stem Cell Phenotype.

Metastasis is a major obstacle to the efficient and successful treatment of cancer. Initiation of metastasis requires epithelial-mesenchymal transition (EMT) that is regulated by several transcription factors, including Snail and ZEB1/2. EMT is closely linked to the acquisition of cancer stem cell (CSC) properties and chemoresistance, which contribute to tumor malignancy. Tumor suppressor p53 inhibits EMT and metastasis by negatively regulating several EMT-inducing transcription factors and regulatory molecules; thus, its inhibition is crucial in EMT, invasion, metastasis, and stemness. Metabolic alterations are another hallmark of cancer. Most cancer cells are more dependent on glycolysis than on mitochondrial oxidative phosphorylation for their energy production, even in the presence of oxygen. Cancer cells enhance other oncogenic metabolic pathways, such as glutamine metabolism, pentose phosphate pathway, and the synthesis of fatty acids and cholesterol. Metabolic reprogramming in cancer is regulated by the activation of oncogenes or loss of tumor suppressors that contribute to tumor progression. Oncogenic metabolism has been recently linked closely with the induction of EMT or CSC phenotypes by the induction of several metabolic enzyme genes. In addition, several transcription factors and molecules involved in EMT or CSCs, including Snail, Dlx-2, HIF-1α, STAT3, TGF-ß, Wnt, and Akt, regulate oncogenic metabolism. Moreover, p53 induces metabolic change by directly regulating several metabolic enzymes. The collective data indicate the importance of oncogenic metabolism in the regulation of EMT, cell invasion and metastasis, and adoption of the CSC phenotype, which all contribute to malignant transformation and tumor development. In this review, we highlight the oncogenic metabolism as a key regulator of EMT and CSC, which is related with tumor progression involving metastasis and chemoresistance. Targeting oncometabolism might be a promising strategy for the development of effective anticancer therapy.

MDL-12330A potentiates TRAIL-induced apoptosis in gastric cancer cells through CHOP-mediated DR5 upregulation.

MDL-12330A is a widely used adenylyl cyclase (AC) inhibitor that blocks AC/cAMP signaling. In this study, we demonstrated a novel antitumor activity of this drug in gastric carcinoma (GC) cell lines. In these GC cells, MDL-12330A reduced cell viability and induced cell death in a concentration-dependent manner. At a moderate concentration (~20 µM), MDL-12330A mainly induced apoptotic death whereas at concentrations greater than 20 µM, it increased non-apoptotic cell death. The induction of apoptosis was at least partially regulated by CHOP-mediated DR5 upregulation, as detected by immunoblotting and gene interference assays. More importantly, low concentrations of MDL-12330A effectively enhanced recombinant human tumor necrosis factor (TNF)-related apoptosis-inducing ligand (rhTRAIL)-induced apoptosis and clonogenicity in these gastric cancer cells. This study demonstrates a possible role of MDL-12330A as a potential sensitizer to TRAIL, and suggests a novel therapeutic strategy targeting gastric cancer cells.

Andrographolide induces apoptotic and non-apoptotic death and enhances tumor necrosis factor-related apoptosis-inducing ligand-mediated apoptosis in gastric cancer cells.

Andrographolide, a natural compound isolated from Andrographis paniculata, has been reported to possess antitumor activity. In the present study, the effect of andrographolide in human gastric cancer (GC) cells was investigated. Andrographolide induced cell death with apoptotic and non-apoptotic features. At a low concentration, andrographolide potentiated apoptosis and reduction of clonogenicity triggered by recombinant human tumor necrosis factor-related apoptosis-inducing ligand (rhTRAIL). Exposure of GC cells to andrographolide altered the expression level of several growth-inhibiting and apoptosis-regulating proteins, including death receptors. It was demonstrated that activity of the TRAIL-R2 (DR5) pathway was critical in the development of andrographolide-mediated rhTRAIL sensitization, since its inhibition significantly reduced the extent of apoptosis induced by the combination of rhTRAIL and andrographolide. In addition, andrographolide increased reactive oxygen species (ROS) generation in a dose-dependent manner. N-acetyl cysteine prevented andrographolide-mediated DR5 induction and the apoptotic effect induced by the combination of rhTRAIL and andrographolide. Collectively, the present study demonstrated that andrographolide enhances TRAIL-induced apoptosis through induction of DR5 expression. This effect appears to involve ROS generation in GCs.

Induction of metastasis, cancer stem cell phenotype, and oncogenic metabolism in cancer cells by ionizing radiation.

Radiation therapy is one of the major tools of cancer treatment, and is widely used for a variety of malignant tumours. Radiotherapy causes DNA damage directly by ionization or indirectly via the generation of reactive oxygen species (ROS), thereby destroying cancer cells. However, ionizing radiation (IR) paradoxically promotes metastasis and invasion of cancer cells by inducing the epithelial-mesenchymal transition (EMT). Metastasis is a major obstacle to successful cancer therapy, and is closely linked to the rates of morbidity and mortality of many cancers. ROS have been shown to play important roles in mediating the biological effects of IR. ROS have been implicated in IR-induced EMT, via activation of several EMT transcription factors-including Snail, HIF-1, ZEB1, and STAT3-that are activated by signalling pathways, including those of TGF-ß, Wnt, Hedgehog, Notch, G-CSF, EGFR/PI3K/Akt, and MAPK. Cancer cells that undergo EMT have been shown to acquire stemness and undergo metabolic changes, although these points are debated. IR is known to induce cancer stem cell (CSC) properties, including dedifferentiation and self-renewal, and to promote oncogenic metabolism by activating these EMT-inducing pathways. Much accumulated evidence has shown that metabolic alterations in cancer cells are closely associated with the EMT and CSC phenotypes; specifically, the IR-induced oncogenic metabolism seems to be required for acquisition of the EMT and CSC phenotypes. IR can also elicit various changes in the tumour microenvironment (TME) that may affect invasion and metastasis. EMT, CSC, and oncogenic metabolism are involved in radioresistance; targeting them may improve the efficacy of radiotherapy, preventing tumour recurrence and metastasis. This study focuses on the molecular mechanisms of IR-induced EMT, CSCs, oncogenic metabolism, and alterations in the TME. We discuss how IR-induced EMT/CSC/oncogenic metabolism may promote resistance to radiotherapy; we also review efforts to develop therapeutic approaches to eliminate these IR-induced adverse effects.

Involvement of DR4/JNK pathway-mediated autophagy in acquired TRAIL resistance in HepG2 cells.

Although tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising anticancer agent, a number of cancer cells demonstrate TRAIL resistance. To date, various molecular targets leading to TRAIL resistance have been elucidated by many researchers, but the mechanisms involved are still not fully understood. In the present study, we obtained TRAIL-resistant cells from the human hepatocellular carcinoma cell line HepG2 by exposing cells to recombinant human TRAIL (rhTRAIL), and determined a mechanism for TRAIL resistance. The selected TRAIL-resistant cells (HepG2-TR) were insensitive to rhTRAIL and triggered autophagy in response to rhTRAIL. The inhibition of autophagy by 3-methyladenine or the knockdown of ATG5 partially restored rhTRAIL-induced apoptosis and cytotoxicity, indicating that protective autophagy occurred in the cells. Notably, rhTRAIL-induced autophagy was mediated through DR4 in HepG2-TR cells, but not in parental HepG2 cells. In addition, the c-Jun N-terminal kinase was involved in DR4-mediated autophagy in HepG2-TR cells. Our results suggest a novel mechanism of TRAIL resistance which is regulated through alterations in DR4 function, which may extend our understanding of the mechanisms of TRAIL resistance.