ATDC binds to KEAP1 to drive NRF2-mediated tumorigenesis and chemoresistance in pancreatic cancer.

Pancreatic ductal adenocarcinoma is a lethal disease characterized by late diagnosis, propensity for early metastasis and resistance to chemotherapy. Little is known about the mechanisms that drive innate therapeutic resistance in pancreatic cancer. The ataxia-telangiectasia group D-associated gene (ATDC) is overexpressed in pancreatic cancer and promotes tumor growth and metastasis. Our study reveals that increased ATDC levels protect cancer cells from reactive oxygen species (ROS) via stabilization of nuclear factor erythroid 2-related factor 2 (NRF2). Mechanistically, ATDC binds to Kelch-like ECH-associated protein 1 (KEAP1), the principal regulator of NRF2 degradation, and thereby prevents degradation of NRF2 resulting in activation of a NRF2-dependent transcriptional program, reduced intracellular ROS and enhanced chemoresistance. Our findings define a novel role of ATDC in regulating redox balance and chemotherapeutic resistance by modulating NRF2 activity.

The kinesin-14 family motor protein KIFC2 promotes prostate cancer progression by regulating p65.

The kinesin-14 motor proteins play important roles in tumor development and drug resistance and have been reported as potential biomarkers or therapeutic targets for tumor treatment. However, kinesin family member C2 (KIFC2), one of the kinesin-14 motor family members, remains largely unknown in prostate cancer (PCa) progression. Here, we used the GEO and The Cancer Genome Atlas datasets, Western blotting, and immunohistochemistry analyses to detect KIFC2 expression in PCa tissues. Additionally, a series of in vivo and in vitro experiments were utilized to demonstrate the roles of KIFC2 in PCa cells. We found that KIFC2 was highly expressed and positively correlated with the clinicopathological characteristics in PCa. Functional experiments indicated that KIFC2 could promote PCa progression. Furthermore, we performed an analysis of the KEGG and GSEA databases, subcellular fractionation, and immunofluorescence to investigate the potential mechanisms of KIFC2 in PCa. We confirmed that KIFC2 could regulate the NF-κB pathway via mediating NF-κB p65 protein expression and nuclear translocation thereby promoting PCa progression and chemotherapeutic resistance. Together, our results suggest that KIFC2 is overexpressed in PCa. By regulating the NF-κB pathway, KIFC2 may play a crucial role in PCa.

PCTAIRE1 promotes mitotic progression and resistance against antimitotic and apoptotic signals.

PCTAIRE1 (also known as CDK16) is a serine-threonine kinase implicated in physiological processes like neuronal development, vesicle trafficking, spermatogenesis and cell proliferation. However, its exact role in cell division remains unclear. In this study, using a library screening approach, we identified PCTAIRE1 among several candidates that resisted mitotic arrest and mitotic cell death induced by polyomavirus small T (PolST) expression in mammalian cells. Our study showed that PCTAIRE1 is a mitotic kinase that localizes at centrosomes during G2 and at spindle poles as the cells enter mitosis, and then at the midbody during cytokinesis. We also report that PCTAIRE1 protein levels fluctuate through the cell cycle and reach their peak at mitosis, during which there is an increase in PCTAIRE1 phosphorylation as well. Interestingly, knockdown of PCTAIRE1 resulted in aberrant mitosis by interfering with spindle assembly and chromosome segregation. Further, we found that PCTAIRE1 promotes resistance of cancer cells to antimitotic drugs, and this underscores the significance of PCTAIRE1 as a potential drug target for overcoming chemotherapeutic resistance. Taken together, these studies establish PCTAIRE1 as a critical mediator of mitotic progression and highlight its role in chemotherapeutic resistance. This article has an associated First Person interview with the first author of the paper.

Cuproptosis enhances docetaxel chemosensitivity by inhibiting autophagy via the DLAT/mTOR pathway in prostate cancer.

Cuproptosis, a newly discovered programmed cell death induced by copper ions, is associated with the progression and drug resistance of various tumors. Docetaxel plays a vital role as a first-line chemotherapeutic agent for advanced prostate cancer; however, most patients end up with prostate cancer progression because of inherent or acquired resistance. Herein, we examined the role of cuproptosis in the chemotherapeutic resistance of prostate cancer to docetaxel. We treated prostate cancer cell lines with elesclomol-CuCl2 , as well as with docetaxel. We performed analyses of CCK8, colony formation tests, cell cycle flow assay, transmission electron microscopy, and mTOR signaling in treated cells, and treated a xenograft prostate cancer model with elesclomol-CuCl2 and docetaxel in vivo, and performed immunohistochemistry and Western blotting analysis in treated tumors. We found that elesclomol-CuCl2 could promote cell death and enhance chemosensitivity to docetaxel. Elesclomol-CuCl2 induced cell death and inhibited the growth of prostate cancer cells relying on copper ions-induced cuproptosis, not elesclomol. In addition, dihydrolipoamide S-acetyltransferase (DLAT) was involved in cuproptosis-enhanced drug sensitivity to docetaxel. Mechanistically, upregulated DLAT by cuproptosis inhibited autophagy, promoted G2/M phase retention of cells, and enhanced the sensitivity to docetaxel chemotherapy in vitro and in vivo via the mTOR signaling pathway. Our findings demonstrated that the cuproptosis-regulated DLAT/mTOR pathway inhibited autophagy and promoted cells in G2/M phase retention, thus enhancing the chemosensitivity to docetaxel. This discovery may provide an effective therapeutic option for treating advanced prostate cancer by inhibiting the chemotherapeutic resistance to docetaxel.

Treating cancer through modulating exosomal protein loading and function: The prospects of natural products and traditional Chinese medicine.

Exosomes, small yet vital extracellular vesicles, play an integral role in intercellular communication. They transport critical components, such as proteins, lipid bilayers, DNA, RNA, and glycans, to target cells. These vesicles are crucial in modulating the extracellular matrix and orchestrating signal transduction processes. In oncology, exosomes are pivotal in tumor growth, metastasis, drug resistance, and immune modulation within the tumor microenvironment. Exosomal proteins, noted for their stability and specificity, have garnered widespread attention. This review delves into the mechanisms of exosomal protein loading and their impact on tumor development, with a focus on the regulatory effects of natural products and traditional Chinese medicine on exosomal protein loading and function. These insights not only offer new strategies and methodologies for cancer treatment but also provide scientific bases and directions for future clinical applications.

Warburg effect enhanced by AKR1B10 promotes acquired resistance to pemetrexed in lung cancer-derived brain metastasis.

BACKGROUND: Resistance to pemetrexed (PEM), a rare chemotherapeutic agent that can efficiently cross the blood-brain barrier, limits the therapeutic efficacy for patients with lung cancer brain metastasis (BM). Aldo-keto reductase family 1 B10 (AKR1B10) was recently found to be elevated in lung cancer BM. The link between AKR1B10 and BM-acquired PEM is unknown. METHODS: PEM drug-sensitivity was assessed in the preclinical BM model of PC9 lung adenocarcinoma cells and the BM cells with or without AKR1B10 interference in vitro and in vivo. Metabolic reprogramming of BM attributed to AKR1B10 was identified by chromatography-mass spectrometry (GC-MS) metabolomics, and the mechanism of how AKR1B10 mediates PEM chemoresistance via a way of modified metabolism was revealed by RNA sequencing as well as further molecular biology experimental approaches. RESULTS: The lung cancer brain metastatic subpopulation cells (PC9-BrM3) exhibited significant resistance to PEM and silencing AKR1B10 in PC9-BrM3 increased the PEM sensitivity in vitro and in vivo. Metabolic profiling revealed that AKR1B10 prominently facilitated the Warburg metabolism characterized by the overproduction of lactate. Glycolysis regulated by AKR1B10 is vital for the resistance to PEM. In mechanism, AKR1B10 promoted glycolysis by regulating the expression of lactate dehydrogenase (LDHA) and the increased lactate, acts as a precursor that stimulates histone lactylation (H4K12la), activated the transcription of CCNB1 and accelerated the DNA replication and cell cycle. CONCLUSIONS: Our finding demonstrates that AKR1B10/glycolysis/H4K12la/CCNB1 promotes acquired PEM chemoresistance in lung cancer BM, providing novel strategies to sensitize PEM response in the treatment of lung cancer patients suffering from BM.

Potential use of EGFR-targeted molecular therapies for tumor suppressor CYLD-negative and poor prognosis oral squamous cell carcinoma with chemoresistance.

BACKGROUND: Tumor suppressor CYLD dysfunction by loss of its expression, triggers malignant transformation, especially drug resistance and tumor invasion/metastasis. Although loss of CYLD expression is significantly associated with poor prognosis in a large variety of tumors, no clinically-effective treatment for CYLD-negative cancer patients is available. METHODS: We focused on oral squamous cell carcinoma (OSCC), and sought to develop novel therapeutic agents for CYLD-negative cancer patients with poor prognosis. CYLD-knockdown OSCC cells by using CYLD-specific siRNA, were used to elucidate and determine the efficacy of novel drug candidates by evaluating cell viability and epithelial-mesenchymal transition (EMT)-like change. Therapeutic effects of candidate drug on cell line-derived xenograft (CDX) model and usefulness of CYLD as a novel biomarker using patient-derived xenograft (PDX) model were further investigated. RESULTS: CYLD-knockdown OSCC cells were resistant for all currently-available cytotoxic chemotherapeutic agents for OSCC, such as, cisplatin, 5-FU, carboplatin, docetaxel, and paclitaxel. By using comprehensive proteome analysis approach, we identified epidermal growth factor receptor (EGFR), a receptor tyrosine kinase, played key roles in CYLD-knockdown OSCC cells. Indeed, cell survival rate in the cisplatin-resistant CYLD-knockdown OSCC cells was markedly inhibited by treatment with clinically available EGFR tyrosine kinase inhibitors (EGFR-TKIs), such as gefitinib. In addition, gefitinib was significantly effective for not only cell survival, but also EMT-like changes through inhibiting transforming growth factor-ß (TGF-ß) signaling in CYLD-knockdown OSCC cells. Thereby, overall survival of CYLD-knockdown CDX models was significantly prolonged by gefitinib treatment. Moreover, we found that CYLD expression was significantly associated with gefitinib response by using PDX models. CONCLUSIONS: Our results first revealed that EGFR-targeted molecular therapies, such as EGFR-TKIs, could have potential to be novel therapeutic agents for the CYLD-negative OSCC patients with poor prognosis.

Exosomal miR-625-3p secreted by cancer-associated fibroblasts in colorectal cancer promotes EMT and chemotherapeutic resistance by blocking the CELF2/WWOX pathway.

Migration, invasion, epithelial-mesenchymal transformation (EMT), and chemotherapeutic resistance are the leading causes of therapeutic failure in people with colorectal cancer (CRC). The migration of exosomal miRNA between cancer cells and the tumor microenvironment is directly associated with malignant behavior in cancer-associated fibroblasts (CAFs). In the context of earlier research, the purpose of the current study was to assess the role and potential mechanism of miR-625-3p released by CAFs in CRC cells. Exosomes were extracted and purified from CAFs conditioned medium by ultracentrifugation. Western blot, immunohistochemistry, CCK-8, transwell assay, H&E staining, Tunnel, real-time PCR, double luciferase assay, RNA-binding protein immunoprecipitation (RIP), and immunofluorescence double staining experiments were used to investigate the effects of CAFs-Exo and miR-625-3p on CRC cell invasion, migration, proliferation, EMT, chemotherapeutic resistance, and molecular mechanisms. The current results indicated that CAFs-Exo was directly internalized by CRC cells, and exosomal miR-625-3p derived from CAFs might promote migration, invasion, EMT and chemotherapeutic resistance in CRC cells by inhibiting the CELF2/WWOX pathway, providing a potential candidate for CRC prediction and treatment.

Mechanisms of chemotherapeutic resistance and the application of targeted nanoparticles for enhanced chemotherapy in colorectal cancer.

Colorectal cancer is considered one of the major malignancies that threaten the lives and health of people around the world. Patients with CRC are prone to post-operative local recurrence or metastasis, and some patients are advanced at the time of diagnosis and have no chance for complete surgical resection. These factors make chemotherapy an indispensable and important tool in treating CRC. However, the complex composition of the tumor microenvironment and the interaction of cellular and interstitial components constitute a tumor tissue with high cell density, dense extracellular matrix, and high osmotic pressure, inevitably preventing chemotherapeutic drugs from entering and acting on tumor cells. As a result, a novel drug carrier system with targeted nanoparticles has been applied to tumor therapy. It can change the physicochemical properties of drugs, facilitate the crossing of drug molecules through physiological and pathological tissue barriers, and increase the local concentration of nanomedicines at lesion sites. In addition to improving drug efficacy, targeted nanoparticles also reduce side effects, enabling safer and more effective disease diagnosis and treatment and improving bioavailability. In this review, we discuss the mechanisms by which infiltrating cells and other stromal components of the tumor microenvironment comprise barriers to chemotherapy in colorectal cancer. The research and application of targeted nanoparticles in CRC treatment are also classified.

Anti-cancer potential of cannabis terpenes in a Taxol-resistant model of breast cancer.

Chemotherapeutic resistance can limit breast cancer outcomes; therefore, the exploration of novel therapeutic options is warranted. Isolated compounds found in cannabis have previously been shown to exhibit anti-cancer effects, but little is known about their effects in resistant breast cancer. Our study aimed to evaluate the effects of terpenes found in cannabis in in vitro chemotherapy-resistant model of breast cancer. We aimed to identify whether five terpenes found in cannabis produced anti-cancer effects, and whether their effects were improved upon co-treatment with cannabinoids and flavonoids also found in cannabis. Nerolidol and ß-caryophyllene produced the greatest cytotoxic effects, activated the apoptotic cascade, and reduced cellular invasion. Combinations with the flavonoid kaempferol potentiated the cytotoxic effects of ocimene, terpinolene, and ß-myrcene. Combinations of nerolidol and Δ9-tetrahydrocannabinol or cannabidiol produced variable responses ranging from antagonism and additivity to synergy, depending on concentrations used. Our results indicate that cannabis terpenes, alone or combined with cannabinoids and flavonoids, produced anti-cancer effects in chemotherapy-resistant breast cancer cell lines. This study is a first step in the identification of compounds that could have therapeutic potential in the treatment of resistant breast cancer.

A nanomechanical strategy involving focal adhesion kinase for overcoming drug resistance in breast cancer.

Despite implementation of nanomechanical studies in cancer research, studies on the nanomechanical aspects of drug resistance in cancer are lacking. Here, we established the mechanical signatures of drug-resistant breast cancer cells using atomic force microscopy-based indentation techniques and functionalized nanopatterned substrates (NPS). Additionally, we examined the expression of proteins pertinent to focal adhesions in order to elucidate the molecular signatures responsible for the acquisition of drug resistance in breast cancer cells. Drug-resistant breast cancer cells exhibited mechanical reinforcement, increased actin stress fibers, dysfunctional mechano-reciprocal interaction with the NPS, vinculin overexpression, and improved focal adhesion kinase (FAK) activity. Owing to differences in FAK activation upon co-treatment with a FAK inhibitor, the drug-resistant breast cancer cells were eradicated more efficiently than invasive breast cancer cells having pro-survival activity. These findings demonstrated the potential of a novel co-treatment regimen using FAK inhibitors for overcoming drug resistance in breast cancer cells.

High L-Type Amino Acid Transporter 1 Levels Are Associated with Chemotherapeutic Resistance in Gastric Cancer Patients.

INTRODUCTION: We investigated whether the expression of L-type amino acid transporter 1 (LAT-1) in clinical gastric cancer (GC) patients could predict patient therapeutic response to postoperative adjuvant chemotherapy. METHODS: Immunohistochemistry was used to investigate LAT-1, CD98, and phosphorylated-mammalian target of rapamycin (p-mTOR) expression in 111 GC patients. To clarify whether LAT-1 influences the therapeutic effects of chemotherapy, the correlation between disease-free survival rates and LAT-1 was determined in 2 groups: 59 patients who did not undergo postoperative adjuvant chemotherapy and 52 patients who did undergo postoperative adjuvant chemotherapy. RESULTS: LAT-1 was significantly correlated with CD98 and p-mTOR expressions. We did not find any statistically significant correlation between LAT-1 and recurrence in the nontreated group. In contrast, a significant association was found between LAT-1 expression and disease-free survival in the chemotherapy group. Moreover, multivariate regression analysis demonstrated that LAT-1 was an independent predictor of disease-free survival in the postoperative adjuvant chemotherapy group (p = 0.012). CONCLUSION: Our findings demonstrate that LAT-1 is a useful predictive marker for a successful postoperative adjuvant chemotherapy treatment.

Effects of miR-224-5p-enhanced downregulation of pannexin-1 on docetaxel-induced apoptosis in amoeboid-like CD44high oral cancer cells.

We previously found that microRNAs play major roles in the maintenance of amoeboid-like oral squamous cell carcinoma (OSCC) cells with high expression of CD44 (CD44high ). However, the roles of microRNAs in chemotherapeutic resistance exhibited by CD44high amoeboid-like OSCC cells are unclear. Here, docetaxel-induced apoptosis was examined in CD44high OSCC cells (CD44high OM-1 cells) cultured on laminin-coated silicone gel. Amoeboid-like CD44high OSCC cells exhibited robust resistance to docetaxel-induced apoptosis and significant upregulation of miR-224-5p expression compared with epithelial-like CD44high OSCC cells and mesenchymal-like CD44high OSCC cells. The expression of pannexin-1 (PANX1), a channel-forming protein that regulates the release of ATP, was significantly upregulated following transfection of amoeboid-like CD44high OSCC cells with an miR-224-5p inhibitor. These results suggest that miR-224-5p inhibits PANX1 expression. Furthermore, miR-224-5p inhibitor-transfected amoeboid-like CD44high OSCC cells exhibited significant enhancement of the proportion of apoptotic cells; however, this effect was significantly inhibited by knockdown of PANX1 with PANX1 small interfering RNA. Additionally, the miR-224-5p inhibitor-enhanced extracellular ATP levels were significantly reduced by PANX1 knockdown. These findings imply that miR-224-5p plays a vital role in the resistance to docetaxel-induced apoptosis by attenuating PANX1-induced ATP discharge. Moreover, amoeboid-like CD44high OSCC cells may be involved in chemotherapeutic resistance of OSCC.

Glutathione S-Transferase M3 Is Associated with Glycolysis in Intrinsic Temozolomide-Resistant Glioblastoma Multiforme Cells.

Glioblastoma multiforme (GBM) is a malignant primary brain tumor. The 5-year relative survival rate of patients with GBM remains <30% on average despite aggressive treatments, and secondary therapy fails in 90% of patients. In chemotherapeutic failure, detoxification proteins are crucial to the activity of chemotherapy drugs. Usually, glutathione S-transferase (GST) superfamily members act as detoxification enzymes by activating xenobiotic metabolites through conjugation with glutathione in healthy cells. However, some overexpressed GSTs not only increase GST activity but also trigger chemotherapy resistance and tumorigenesis-related signaling transductions. Whether GSTM3 is involved in GBM chemoresistance remains unclear. In the current study, we found that T98G, a GBM cell line with pre-existing temozolomide (TMZ) resistance, has high glycolysis and GSTM3 expression. GSTM3 knockdown in T98G decreased glycolysis ability through lactate dehydrogenase A activity reduction. Moreover, it increased TMZ toxicity and decreased invasion ability. Furthermore, we provide next-generation sequencing-based identification of significantly changed messenger RNAs of T98G cells with GSTM3 knockdown for further research. GSTM3 was downregulated in intrinsic TMZ-resistant T98G with a change in the expression levels of some essential glycolysis-related genes. Thus, GSTM3 was associated with glycolysis in chemotherapeutic resistance in T98G cells. Our findings provide new insight into the GSTM3 mechanism in recurring GBM.

Luminescent PtII and PtIV Platinacycles with Anticancer Activity Against Multiplatinum-Resistant Metastatic CRC and CRPC Cell Models.

Platinum-based chemotherapy persists to be the only effective therapeutic option against a wide variety of tumours. Nevertheless, the acquisition of platinum resistance is utterly common, ultimately cornering conventional platinum drugs to only palliative in many patients. Thus, encountering alternatives that are both effective and non-cross-resistant is urgent. In this work, we report the synthesis, reduction studies, and luminescent properties of a series of cyclometallated (C,N,N')PtIV compounds derived from amine-imine ligands, and their remarkable efficacy at the high nanomolar range and complete lack of cross-resistance, as an intrinsic property of the platinacycle, against multiplatinum-resistant colorectal cancer (CRC) and castration-resistant prostate cancer (CRPC) metastatic cell lines generated for this work. We have also determined that the compounds are effective and selective for a broader cancer panel, including breast and lung cancer. Additionally, selected compounds have been further evaluated, finding a shift in their antiproliferative mechanism towards more cytotoxic and less cytostatic than cisplatin against cancer cells, being also able to oxidize cysteine residues and inhibit topoisomerase II, thereby holding great promise as future improved alternatives to conventional platinum drugs.

CCN2 promotes drug resistance in osteosarcoma by enhancing ABCG2 expression.

In recent years, osteosarcoma survival rates have failed to improve significantly with conventional treatment modalities because of the development of chemotherapeutic resistance. The human breast cancer resistance protein/ATP binding cassette subfamily G member 2 (BCRP/ABCG2), a member of the ATP-binding cassette family, uses ATP hydrolysis to expel xenobiotics and chemotherapeutics from cells. CCN family member 2 (CCN2) is a secreted protein that modulates the biological function of cancer cells, enhanced ABCG2 protein expression and activation in this study via the α6ß1 integrin receptor and increased osteosarcoma cell viability. CCN2 treatment downregulated miR-519d expression, which promoted ABCG2 expression. In a mouse xenograft model, knockdown of CCN2 expression increased the therapeutic effect of doxorubicin, which was reversed by ABCG2 overexpression. Our data show that CCN2 increases ABCG2 expression and promotes drug resistance through the α6ß1 integrin receptor, whereas CCN2 downregulates miR-519d. CCN2 inhibition may represent a new therapeutic concept in osteosarcoma.

RAB13 as a novel prognosis marker promotes proliferation and chemotherapeutic resistance in gastric cancer.

Gastric cancer (GC) is still a major lethal gastrointestinal tumor. In this study, we clarified that RAB13, which is a member of Rab GTPase family and responsible for cargos delivery between the Golgi and the plasma membrane, plays critical roles in the proliferation and the chemotherapeutic resistance in GC cells. Analyzing RAB13 expression in GC specimens, we found that its mRNA level was higher in cancerous tissues compared with normal counterparts and this increase was further associated with malignant progression of GC. Moreover, increased RAB13 indicated poor overall survival (OS) and progression free survival (PFS) in GC patients. We then found that deletion of RAB13 inhibited the proliferation and promoted the apoptosis in AGS and NCI-N87 cells, the impairments of viability which was due to reduced amount of RAB13 anchoring the plasma membrane and attenuated cellular response to EGF treatment and the activation of downstream Akt/ERK/mTOR signaling pathways accordingly. Moreover, in vitro experiments showed that RAB13 deletion enhanced the sensitization of AGS and NCI-N87 cells toward cisplatin (CDDP) and 5-fluorouracil (5-FU) treatment respectively. Together, these data demonstrate that RAB13 promotes the proliferation and confers CDDP and 5-FU resistance to GC cells, which provides experimental support to target this protein in future clinical practice.

MBD1 promotes the malignant behavior of gallbladder cancer cells and induces chemotherapeutic resistance to gemcitabine.

BACKGROUND: Methyl-CpG binding domain protein 1 (MBD1), which couples DNA methylation to transcriptional repression, has been implicated in transcriptional regulation, heterochromatin formation, genomic stability, cell cycle progression and development. It has also been proven that MBD1 is involved in tumor development and progression. However, whether MBD1 is involved in tumorigenesis, especially in gallbladder cancer, is totally unknown. METHODS: Human GBC-SD and SGC996 cells were used to perform experiments. Invasion, wound healing and colony formation assays were performed to evaluate cell viability. A CCK-8 assay was performed to assess gallbladder cancer cell viability after gemcitabine treatment. Western blot analysis was used to evaluate changes in protein expression. Human gallbladder cancer tissues and adjacent nontumor tissues were subjected to immunohistochemical staining to detect protein expression. RESULTS: We found that MBD1 expression was significantly upregulated in gallbladder cancer tissues compared with that in surrounding normal tissues according to immunohistochemical analysis of 84 surgically resected gallbladder cancer specimens. These data also indicated that higher MBD1 expression was correlated with lymph node metastasis and poor survival in gallbladder cancer patients. Overexpression and deletion in vitro validated MBD1 as a potent oncogene promoting malignant behaviors in gallbladder cancer cells, including invasion, proliferation and migration, as well as epithelial-mesenchymal transition. Studies have demonstrated that epithelial-mesenchymal transition is common in gallbladder cancer, and it is well known that drug resistance and epithelial-mesenchymal transition are very closely correlated. Herein, our data show that targeting MBD1 restored gallbladder cancer cell sensitivity to gemcitabine chemotherapy. CONCLUSIONS: Taken together, the results of our study revealed a novel function of MBD1 in gallbladder cancer tumor development and progression through participation in the gallbladder cancer epithelial-mesenchymal transition program, which is involved in resistance to gemcitabine chemotherapy. Thus, MBD1 may be a potential therapeutic target for gallbladder cancer.

Capitalizing on competition: An evolutionary model of competitive release in metastatic castration resistant prostate cancer treatment.

The development of chemotherapeutic resistance resulting in tumor relapse is largely the consequence of the mechanism of competitive release of pre-existing resistant tumor cells selected for regrowth after chemotherapeutic agents attack the previously dominant chemo-sensitive population. We introduce a prisoner's dilemma game theoretic mathematical model based on the replicator of three competing cell populations: healthy (cooperators), sensitive (defectors), and resistant (defectors) cells. The model is shown to recapitulate prostate-specific antigen measurement data from three clinical trials for metastatic castration-resistant prostate cancer patients treated with 1) prednisone, 2) mitoxantrone and prednisone and 3) docetaxel and prednisone. Continuous maximum tolerated dose schedules reduce the sensitive cell population, initially shrinking tumor burden, but subsequently "release" the resistant cells from competition to re-populate and re-grow the tumor in a resistant form. The evolutionary model allows us to quantify responses to conventional (continuous) therapeutic strategies as well as to design adaptive strategies.These novel adaptive strategies are robust to small perturbations in timing and extend simulated time to relapse from continuous therapy administration.

Disruption of the c-Myc/miR-200b-3p/PRDX2 regulatory loop enhances tumor metastasis and chemotherapeutic resistance in colorectal cancer.

BACKGROUND: Metastasis is a major threat to colorectal cancer (CRC) patients. We have reported that peroxiredoxin-2 (PRDX2) is associated with CRC invasion and metastasis. However, the mechanisms regulating PRDX2 expression remain unclear. We investigate whether microRNAs (miRNAs) regulate PRDX2 expression in CRC progression. METHODS: Quantitative real-time polymerase chain reaction (qPCR) was used to measure microRNA-200b-3p (miR-200b-3p) expression. Immunohistochemistry (IHC) was performed to detect c-Myc and PRDX2 protein levels in CRC tissue samples (n = 97). Western blot was used to quantify PRDX2, c-Myc, AKT2/GSK3ß pathway-associated proteins and epithelial-mesenchymal transition (EMT)-related proteins in CRC cells. Luciferase reporter assays were used to analyze the interaction between miR-200b-3p and 3'untranslated region (3'UTR) of PRDX2 mRNA and AKT2 mRNA as well as c-Myc and the miR-200b-3p promoter. Chromatin immunoprecipitation (ChIP) assay was used to evaluate binding of c-Myc to the miR-200b-3p promoter. Invasive assay and metastatic model were used to assess invasive and metastatic capacities of CRC cells in vitro and in vivo. Moreover, drug-induced apoptosis was measured by flow cytometry. RESULTS: We found that miR-200b-3p was significantly downregulated, whereas c-Myc and PRDX2 were upregulated in metastatic CRC cells and CRC tissues compared to their counterparts. An inverse correlation existed between c-Myc and miR-200b-3p, and between miR-200b-3p and PRDX2. We also found that PRDX2 was a target of miR-200b-3p. Importantly, overexpression of nontargetable PRDX2 eliminated the suppressive effects of miR-200b-3p on proliferation, invasion, EMT, chemotherapeutic resistance and metastasis of CRC cells. Moreover, c-Myc bound to the promoter of miR-200b-3p and repressed its transcription. In turn, miR-200b-3p disrupted the stability of c-Myc protein by inducing c-Myc protein threonine 58 (T58) phosphorylation and serine 62 (S62) dephosphorylation via AKT2/GSK3ß pathway. CONCLUSIONS: Our findings reveal that the c-Myc/miR-200b/PRDX2 loop regulates CRC progression and its disruption enhances tumor metastasis and chemotherapeutic resistance in CRC.