Calmodulin mediates Fas-induced FADD-independent survival signaling in pancreatic cancer cells via activation of Src-extracellular signal-regulated kinase (ERK)

Pancreatic cancer remains a devastating malignancy with a poor prognosis and is largely resistant to current therapies. To understand the resistance of pancreatic tumors to Fas death receptor-induced apoptosis, we investigated the molecular mechanisms of Fas-activated survival signaling in pancreatic cancer cells. We found that knockdown of the Fas-associated protein with death domain (FADD), the adaptor that mediates downstream signaling upon Fas activation, rendered Fas-sensitive MiaPaCa-2 and BxPC-3 pancreatic cells resistant to Fas-induced apoptosis. By contrast, Fas activation promoted the survival of the FADD knockdown MiaPaCa-2 and BxPC-3 cells in a concentration-dependent manner. The pharmacological inhibitor of ERK, PD98059, abrogated Fas-promoted cell survival in FADD knockdown MiaPaCa-2 and BxPC-3 cells. Furthermore, increased phosphorylation of Src was demonstrated to mediate Fas-induced ERK activation and cell survival. Immunoprecipitation of Fas in the FADD knockdown cells identified the presence of increased calmodulin, Src, and phosphorylated Src in the Fas-associated protein complex upon Fas activation. Trifluoperazine, a calmodulin antagonist, inhibited Fas-induced recruitment of calmodulin, Src, and phosphorylated Src. Consistently, trifluoperazine blocked Fas-promoted cell survival. A direct interaction of calmodulin and Src and their binding site were identified with recombinant proteins. These results support an essential role of calmodulin in mediating Fas-induced FADD-independent activation of Src-ERK signaling pathways, which promote survival signaling in pancreatic cancer cells. Understanding the molecular mechanisms responsible for the resistance of pancreatic cells to apoptosis induced by Fas-death receptor signaling may provide molecular insights into designing novel therapies to treat pancreatic tumors.     

Type I interferon-mediated pathway interacts with peroxisome proliferator activated receptor-γ (PPAR-γ): At the cross-road of pancreatic cancer cell proliferation

Pancreatic adenocarcinoma remains an unresolved therapeutic challenge because of its intrinsically refractoriness to both chemo- and radiotherapy due to the complexity of signaling and the activation of survival pathways in cancer cells. Recent studies have demonstrated that the combination of some drugs, targeting most of aberrant pathways crucial for the survival of pancreatic cancer cells may be a valid antitumor strategy for this cancer. Type I interferons (IFNs) may have a role in the pathogenesis and progression of pancreatic adenocarcinoma, but the limit of their clinical use is due to the activation of tumor resistance mechanisms, including JAK-2/STAT-3 pathway. Moreover, aberrant constitutive activation of STAT-3 proteins has been frequently detected in pancreatic adenocarcinoma. The selective targeting of these cell survival cascades could be a promising strategy in order to enhance the antitumor effects of type I IFNs. The activation of peroxisome proliferator-activated receptor γ (PPAR-γ), on the other hand, has a suppressive activity on STAT-3. In fact, PPAR-γ agonists negatively modulate STAT-3 through direct and/or indirect mechanisms in several normal and cancer models. This review provides an overview on the current knowledge about the molecular mechanisms and antitumor activity of these two promising classes of drugs for pancreatic cancer therapy. Finally, the synergistic antiproliferative activity of combined IFN-β and troglitazone treatment on pancreatic cancer cell lines, evaluated in vitro, and the consequent potential clinical applications will be discussed.     

Use of herbal medicines and natural products: An alternative approach to overcoming the apoptotic resistance of pancreatic cancer

Pancreatic cancer has a poor prognosis with a 5-year survival rate of <5%. It does not respond well to either chemotherapy or radiotherapy, due partly to apoptotic resistance (AR) of the cancer cells. AR has been attributed to certain genetic abnormalities or defects in apoptotic signaling pathways. In pancreatic cancer, significant mutations of K-ras and p53, constitutive activation of NFκB, over-expression of heat shock proteins (Hsp90, Hsp70), histone deacetylase (HDACs) and the activities of other proteins (COX-2, Nrf2 and bcl-2 family members) are closely linked with resistance to apoptosis and invasion. AR has also been associated with aberrant signaling of MAPK, PI3K–AKT, JAK/STAT, SHH, Notch, and Wnt/β-catenin pathways. Strategies targeting these signaling molecules and pathways provide an alternative for overcoming AR in pancreatic cancer. The use of herbal medicines or natural products (HM/NPs) alone or in combination with conventional anti-cancer agents has been shown to produce beneficial effects through actions upon multiple molecular pathways involved in AR. The current standard first-line chemotherapeutic agents for pancreatic cancer are gemcitabine (Gem) or Gem-containing combinations; however, the efficacy is dissatisfied and this limitation is largely attributed to AR. Meanwhile, emerging data have pointed to a combination of HM/NPs that may augment the sensitivity of pancreatic cancer cells to Gem. Greater understanding of how these compounds affect the molecular mechanisms of apoptosis may propel development of HM/NPs as anti-cancer agents and/or adjuvant therapies forward.In this review, we give a critical appraisal of the use of HM/NPs alone and in combination with anti-cancer drugs. We also discuss the potential regulatory mechanisms whereby AR is involved in these protective pathways.     

Pancreatic cancer stem cells and relevance to cancer treatments

Pancreatic cancer continues to be a malignancy with few therapeutic options. The majority of patients that present for an evaluation have locally advanced or metastatic disease that is incurable by surgical approaches. Chemotherapy and radiotherapy resistance of pancreatic adenocarcinomas limits the efficacy of these therapeutic approaches. Recent evidence supports the existence of human pancreatic cancer stem cells, which appear to drive tumor initiation and progression and are particularly resistant to cell death induced by radiation or chemotherapy. Understanding the mechanisms of pancreatic cancer stem cell self‐renewal and resistance to standard therapies may lead to new, more effective therapies to treat this dismal disease. J. Cell. Biochem. 107: 40–45, 2009. © 2009 Wiley‐Liss, Inc.     

NUPR1 works against the metabolic stress-induced autophagy-associated cell death in pancreatic cancer cells

The incidence of pancreatic adenocarcinoma is increasing with more than 43,000 predicted new cases in the US and 65,000 in Europe this year. Pancreatic cancer patients have a short life expectancy with less than 3–4% 5-y survival, which results in an equivalent incidence and mortality rate. One of the major challenges in pancreatic cancer is the identification of pharmacological approaches that overcome the resistance of this cancer to therapy. Intensive research in the past decades has led to the classification of pancreatic cancers and the identification of the driver key genetic events. Despite the advances in understanding the molecular mechanisms responsible for pancreatic cancer pathogenesis, this knowledge had little impact on significantly improving the treatment for this dismal disease. In particular, we know today that the lack of therapeutic response in pancreatic cancer is due to the intrinsic high resistance of these tumors to chemotherapy and radiation, rather than to the inappropriate design of these therapeutic approaches. Thus, in order to ensure a better outcome for pancreatic cancer patients, there is a strong need for research focused on the mechanism that determines this resistant phenotype and the means that might drive enhanced response to therapy.     

A global perspective of radiation-induced signal transduction pathways in cancer therapeutics

Radiation is a well established therapeutic modality for the treatment of solid tumors. By merging molecular biological approaches with radiation biology, a significant number of signaling events elicited by ionizing radiation have been delineated. These signaling pathways include events leading to cell cycle arrest, apoptosis or cell survival. There are two major signaling events that affect radiation response. One is the intrinsic/constitutive pro-survival signaling event that is present in proliferating tumor cells while the other is "induced pro-survival event" in response to radiation, both of these events confer resistance to the killing effects of radiation. In this review, signaling pathways that lead to either apoptosis or survival of cells following ionizing radiation are discussed in detail. In addition, mechanisms of action for gene/drug based inhibitors that modulate the expression and function of various genes and gene products involved in pro-survival signaling pathways are described. Further, novel strategies to abrogate the "induced radiation resistance" leading to enhanced therapeutic efficacy of ionizing radiation have been proposed. These novel strategies include the use of radio-gene therapy, low dose fractionated radiation therapy as a chemopotentiator and therapeutic utility of high radiation dose induced bystander effect. The complete understanding of the molecular pathways leading to apoptosis/survival of cells following ionizing radiation will help in tailoring more effective novel strategies and treatment modalities for complete eradication of cancer.     

Metabolism addiction in pancreatic cancer

Pancreatic ductal adenocarcinoma, an aggressively invasive, treatment-resistant malignancy and the fourth leading cause of cancer deaths in the United States, is usually detectable only when already inevitably fatal. Despite advances in genetic screening, mapping and molecular characterization, its pathology remains largely elusive. Renewed research interest in longstanding doctrines of tumor metabolism has led to the emergence of aberrant signaling pathways as critical factors modulating central metabolic networks that fuel pancreatic tumors. Such pathways, including those of Ras signaling, glutamine-regulatory enzymes, lipid metabolism and autophagy, are directly affected by genetic mutations and extreme tumor microenvironments that typify pancreatic tumor cells. Elucidation of these metabolic networks can be expected to yield more potent therapies against this deadly disease.     

Melatonin and pancreatic cancer: Current knowledge and future perspectives

Pancreatic cancer has a high mortality rate due to the absence of early symptoms and subsequent late diagnosis; additionally, pancreatic cancer has a high resistance to radio- and chemotherapy. Multiple inflammatory pathways are involved in the pathophysiology of pancreatic cancer. Melatonin an indoleamine produced in the pineal gland mediated and receptor-independent action is the pancreas and other where has both receptors. Melatonin is a potent antioxidant and tissue protector against inflammation and oxidative stress. In vivo and in vitro studies have shown that melatonin supplementation is an appropriate therapeutic approach for pancreatic cancer. Melatonin may be an effective apoptosis inducer in cancer cells through regulation of a large number of molecular pathways including oxidative stress, heat shock proteins, and vascular endothelial growth factor. Limited clinical studies, however, have evaluated the role of melatonin in pancreatic cancer. This review summarizes what is known regarding the effects of melatonin on pancreatic cancer and the mechanisms involved.     

CMTM家族成员在肿瘤细胞中的分子机制及潜在临床价值

恶性肿瘤已成为危害人类健康的重要杀手,针对肿瘤的研究也成为当今医学界的热点.含有MARVEL跨膜结构域的趋化素样因子基因家族(CKLF-like MARVEL transmembrane domain containing family of genes,CMTM family),原名人类趋化素样因子超家族(chemo...     

Cancer cells stemness: A doorstep to targeted therapy

Recent advances in research on cancer have led to understand the pathogenesis of cancer and development of new anticancer drugs. Despite of these advancements, many tumors have been found to recur, undergo metastasis and develop resistance to therapy. Accumulated evidences suggest that small population of cancer cells known as cancer stem cells (CSC) are responsible for reconstitution and propagation of the disease. CSCs possess the ability to self-renew, differentiate and proliferate like normal stem cells. CSCs also appear to have resistance to anti-cancer therapies and subsequent relapse. The underlying stemness properties of the CSCs are reliant on multiple molecular targets such as signaling pathways, cell surface molecules, tumor microenvironment, apoptotic pathways, microRNA, stem cell differentiation, and drug resistance markers. Thus an effective therapeutic strategy relies on targeting CSCs to overcome the possible tumor relapse and chemoresistance. The targeted inhibition of these stem cell biomarkers is one of the promising approaches to eliminate cancer stemness. This review article summarizes possible targets of cancer cell stemness for the complete treatment of cancer.     

Reduction of Decoy Receptor 3 Enhances TRAIL-Mediated Apoptosis in Pancreatic Cancer

Most human pancreatic cancer cells are resistant to tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis. However, the mechanisms by which pancreatic cancer cells utilize their extracellular molecules to counteract the proapoptotic signaling mediated by the TNF family are largely unknown. In this study, we demonstrate for the first time that DcR3, a secreted decoy receptor that malignant pancreatic cancer cells express at a high level, acts as an extracellular antiapoptotic molecule by binding to TRAIL and counteracting its death-promoting function. The reduction of DcR3 with siRNA unmasked TRAIL and greatly enhanced TRAIL-induced apoptosis. Gemcitabine, a first-line drug for pancreatic cancer, also reduced the level of DcR3. The addition of DcR3 siRNA further enhanced gemcitabine-induced apoptosis. Notably, our in vivo study demonstrated that the therapeutic effect of gemcitabine could be enhanced via further reduction of DcR3, suggesting that downregulation of DcR3 in tumor cells could tip the balance of pancreatic cells towards apoptosis and potentially serve as a new strategy for pancreatic cancer therapy.     

Triparanol suppresses human tumor growth in vitro and in vivo

Despite the improved contemporary multidisciplinary regimens treating cancer, majority of cancer patients still suffer from adverse effects and relapse, therefore posing a significant challenge to uncover more efficacious molecular therapeutics targeting signaling pathways central to tumorigenesis. Here, our study have demonstrated that Triparanol, a cholesterol synthesis inhibitor, can block proliferation and induce apoptosis in multiple human cancer cells including lung, breast, liver, pancreatic, prostate cancer and melanoma cells, and growth inhibition can be rescued by exogenous addition of cholesterol. Remarkably, we have proved Triparanol can significantly repress Hedgehog pathway signaling in these human cancer cells. Furthermore, study in a mouse xenograft model of human lung cancer has validated that Triparanol can impede tumor growth in vivo. We have therefore uncovered Triparanol as potential new cancer therapeutic in treating multiple types of human cancers with deregulated Hedgehog signaling.     

New insights into pancreatic cancer stem cells

Pancreatic cancer(PC) has been one of the deadliest of all cancers, with almost uniform lethality despite aggressive treatment. Recently, there have been important advances in the molecular, pathological and biological understandingof pancreatic cancer. Even after the emergence of recent new targeted agents and the use of multiple therapeutic combinations, no treatment option is viable in patients with advanced cancer. Developing novel strategies to target progression of PC is of intense interest. A small population of pancreatic cancer stem cells(CSCs) has been found to be resistant to chemotherapy and radiation therapy. CSCs are believed to be responsible for tumor initiation, progression and metastasis. The CSC research has recently achieved much progress in a variety of solid tumors, including pancreatic cancer to some extent. This leads to focus on understanding the role of pancreatic CSCs. The focus on CSCs may offer new targets for prevention and treatment of this deadly cancer. We review the most salient developments in important areas of pancreatic CSCs. Here, we provide a review of current updates and new insights on the role of CSCs in pancreatic tumor progression with special emphasis on Dcl K1 and Lgr5, signaling pathways altered by CSCs, and the role of CSCs in prevention and treatment of PC.     

The role of microRNAs in 5-FU resistance of colorectal cancer: Possible mechanisms

Colorectal cancer (CRC) is one of the most common cancers globally. Despite recent advances in therapeutic approaches, this cancer continues to have a poor prognosis, particularly when diagnosed late. 5-Fluorouracil (5-FU) has been commonly prescribed for patients with CRC, but resistance to 5-FU is one of the main reasons for failure in the treatment of this condition. Recently, microRNAs (miRNAs) have been established as a means of modifying the signaling pathways involved in initiation and progression of CRC and their role as oncogene or tumor suppressor have been investigated in various studies. Moreover, miRNAs through various mechanisms play an important role in inducing tumor resistance or sensitivity to anticancer drugs. Detecting and targeting these mechanisms may be a new therapeutic approach. This review summarizes the current knowledge about the potential roles of miRNAs in 5-FU resistance, with particular emphasis on molecular mechanism involved.     

Pancreatic β-cell regeneration: From molecular mechanisms to therapy

Pancreatic β cells are a type of cells that are present in the islets of Langerhans. These cells are highly specialized for the secretion of insulin in response to low increasing of blood glucose levels. Hence, pancreatic β cells could contribute to maintaining systemic glucose homeostasis. Increasing evidence has revealed that a variety of internal (ie, genetic and epigenetic factors) and external factors (ie, radical-oxidative stress) are involved in the protection and/or regeneration of pancreatic β cells. The pathways regulating β-cell replication have been intensely investigated. Glucose has an important role in cell cycle entry of quiescent β cells, which exerts its effect via glucose metabolism and unfolded proteins. A variety of growth factors, hormones, and signaling pathways (ie, calcium-calcineurin nuclear factor of activated T cells) are others factors that could affect β-cell replication under different conditions. Therefore, a greater understanding of the underlying pathways involved in the regeneration and protection of pancreatic β cells could lead to finding and developing new therapeutic approaches. Utilization of stem cells and various phytochemical agents have provided new aspects for preventing β-cell degeneration and stimulating the endogenous regeneration of islets. Thus, these therapeutic platforms could be used as potential therapies in the treatment of insulin-dependent diabetes mellitus. Here, we summarized the various mechanisms involved in pancreatic β-cell regeneration. Moreover, we highlighted different therapeutic approaches which could be used for the regeneration of pancreatic β cells.     

Protein arginine methylation promotes therapeutic resistance in human pancreatic cancer

Pancreatic cancer is a lethal disease with limited treatment options for cure. A high degree of intrinsic and acquired therapeutic resistance may result from cellular alterations in genes and proteins involved in drug transportation and metabolism, or from the influences of cancer microenvironment. Mechanistic basis for therapeutic resistance remains unclear and should profoundly impact our ability to understand pancreatic cancer pathogenesis and its effective clinical management. Recent evidences have indicated the importance of epigenetic changes in pancreatic cancer, including posttranslational modifications of proteins. We will review new knowledge on protein arginine methylation and its consequential contribution to therapeutic resistance of pancreatic cancer, underlying molecular mechanism, and clinical application of potential strategies of its reversal.