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Publications (60)
Pyrimidine nucleotide biosynthesis is a druggable metabolic dependency of cancer cells, and chemotherapy agents targeting pyrimidine metabolism are the backbone of treatment for many cancers. Dihydroorotate dehydrogenase (DHODH) is an essential enzyme in the de novo pyrimidine biosynthesis pathway that can be targeted by clinically approved inhibit...
The ability of tumour cells to thrive in harsh microenvironments depends on the utilization of nutrients available in the milieu. Here we show that pancreatic cancer-associated fibroblasts (CAFs) regulate tumour cell metabolism through the secretion of acetate, which can be blocked by silencing ATP citrate lyase (ACLY) in CAFs. We further show that...
Nutritional factors play crucial roles in immune responses. The tumor-caused nutritional deficiencies are known to affect antitumor immunity. Here, we demonstrate that pancreatic ductal adenocarcinoma (PDAC) cells can suppress NK-cell cytotoxicity by restricting the accessibility of vitamin B6 (VB6). PDAC cells actively consume VB6 to support one-c...
Pyrimidine nucleotide biosynthesis is a druggable metabolic dependency of cancer cells, and chemotherapy agents targeting pyrimidine metabolism are the backbone of treatment for many cancers. Dihydroorotate dehydrogenase (DHODH) is an essential enzyme in the de novo pyrimidine biosynthesis pathway that can be targeted by clinically approved inhibit...
Pyrimidine nucleotide biosynthesis is a druggable metabolic dependency of cancer cells, and chemotherapy agents targeting pyrimidine metabolism are the backbone of treatment for many cancers. Dihydroorotate dehydrogenase (DHODH) is an essential enzyme in the de novo pyrimidine biosynthesis pathway that can be targeted by clinically approved inhibit...
Pyrimidine nucleotide biosynthesis is a druggable metabolic dependency of cancer cells, and chemotherapy agents targeting pyrimidine metabolism are the backbone of treatment for many cancers. Dihydroorotate dehydrogenase (DHODH) is an essential enzyme in the de novo pyrimidine biosynthesis pathway that can be targeted by clinically approved inhibit...
In response to diverse cellular cues, MAP3K1, a mitogen-activated protein kinase, participates in various cancer signaling networks including the NFκB, JNK, ERK, and p38 pathways. Functioning as a signaling kinase in these oncogenic pathways, MAP3K1 contributes to tumor growth and metastasis, thus making it an attractive therapeutic target for canc...
Inhibitors of dihydroorotate dehydrogenase (DHODH), a key enzyme for de novo synthesis of pyrimidine nucleotides, have failed in clinical trials for various cancers despite robust efficacy in preclinical animal models. To probe for druggable mediators of DHODH inhibitor resistance, we performed a combination screen with a small molecule library aga...
Ecdysoneless (ECD) protein is essential for embryogenesis, cell-cycle progression, and cellular stress mitigation with an emerging role in mRNA biogenesis. We have previously shown that ECD protein as well as its mRNA are overexpressed in breast cancer and ECD overexpression predicts shorter survival in patients with breast cancer. However, the gen...
Metabolic alterations regulate cancer aggressiveness and immune responses. Given the poor response of pancreatic ductal adenocarcinoma (PDAC) to conventional immunotherapies, we investigated the link between metabolic alterations and immunosuppression. Our metabolic enzyme screen indicated that elevated expression of CD73, an ecto-5’–nucleotidase t...
Pancreatic ductal adenocarcinoma (PDAC) patients display distinct phenotypes of cachexia development, with either adipose tissue loss preceding skeletal muscle wasting or loss of only adipose tissue. Activin A levels were measured in serum and analyzed in tumor specimens of both a cohort of Stage IV PDAC patients and the genetically engineered KPC...
Pancreatic ductal adenocarcinoma (PDAC) represents 3% of all cancer cases and 7% of all cancer deaths in the United States. Late diagnosis and inadequate response to standard chemotherapies contribute to an unfavorable prognosis and an overall 5-year survival rate of less than 10% in PDAC. Despite recent advances in tumor immunology, tumor-induced...
Background & Aims
SIRT5 plays pleiotropic roles via post-translational modifications, serving as a tumor suppressor, or an oncogene, in different tumors. However, the role SIRT5 plays in the initiation and progression of pancreatic ductal adenocarcinoma (PDAC) remains unknown.
Methods
Published datasets and tissue arrays with SIRT5 staining were u...
Background:
The mechanistic target of rapamycin complex 1 (mTORC1) is a nutrient-sensing pathway and a key regulator of amino acid and glucose metabolism. Dysregulation of the mTOR pathways is implicated in the pathogenesis of metabolic syndrome, obesity, type 2 diabetes, and pancreatic cancer.
Objectives:
We investigated the impact of inhibitio...
Cancer cachexia patients experience significant muscle wasting, which impairs the quality of life and treatment efficacy for patients. Skeletal muscle protein turnover is imparted by increased expression of ubiquitin-proteasome pathway components. Mitogen-activated protein kinases p38 and ERK have been shown to augment E3 ubiquitin ligase expressio...
Approximately one third of cancer patients die due to complexities related to cachexia. However, the mechanisms of cachexia and the potential therapeutic interventions remain poorly studied. We observed a significant positive correlation between SIRT1 expression and muscle fiber cross-sectional area in pancreatic cancer patients. Rescuing Sirt1 exp...
Incidence of cachexia is highly prevalent in pancreatic ductal adenocarcinoma (PDAC); advanced disease stage directly correlates with decreased muscle and fat mass in PDAC patients. The pancreatic tumor microenvironment is central to the release of systemic factors that govern lipolysis, proteolysis, and muscle and fat degeneration leading to the c...
Pancreatic cancer is the third leading cause of cancer-related deaths in the USA. Pancreatic tumors are characterized by enhanced glycolytic metabolism promoted by a hypoxic tumor microenvironment and a resultant acidic milieu. The metabolic reprogramming allows cancer cells to survive hostile microenvironments. Through the analysis of the principa...
Pancreatic ductal adenocarcinoma (PDAC) has a five-year survival rate of <10% due in part to a lack of effective therapies. Pan-histone deacetylase (HDAC) inhibitors have shown preclinical efficacy against PDAC but have failed in the clinic due to toxicity. Selective HDAC inhibitors may reduce toxicity while retaining therapeutic efficacy. However,...
About eighty percent of pancreatic cancer patients demonstrate excessive loss of skeletal muscles with or without loss of adipose deposits, a condition known as cancer-associated cachexia. Severe complexities related to cancer-associated cachexia contribute to mortality in one-third of pancreatic cancer patients. Multiple factors, including loss of...
p>About eighty percent of pancreatic cancer patients demonstrate excessive loss of skeletal muscles with or without loss of adipose deposits, a condition known as cancer-associated cachexia. Severe complexities related to cancer-associated cachexia contribute to mortality in one-third of pancreatic cancer patients. Multiple factors, including loss...
Cachexia, a complex metabolic syndrome, is characterized by involuntary weight loss along with muscle wasting and fat depletion leading to poor quality of life of patients. About 80% of pancreatic cancer patients exhibit cachectic phenotype at the time of diagnosis. Here, we present the several molecular and physiological parameters, which we utili...
Metabolic reprograming is an established hallmark of cancer cells. Pancreatic cancer cells, by virtue of the underlying oncogenic drivers, demonstrate metabolic reprograming to sustain growth, invasiveness, and therapy resistance. The increased demands of the growing tumor cells alter the metabolic and signaling pathways to meet the growing nutrien...
Pancreatic ductal adenocarcinoma is a devastating malignancy with a five-year survival rate less than 7%. It is characterized by a plethora of metabolic and signaling pathways, which plays a critical role in the pathogenesis of the disease. Caloric restriction and ketogenic diets have been shown to be beneficial in the management of several kinds o...
Cancer-associated cachexia is a complex metabolic syndrome which leads to excessive loss of skeletal muscle and adipose deposits. Up to 80% of pancreatic cancer patients suffer from cachexia and nearly one third die due to complexities related to the syndrome. Treatment of cachexia will not only improve the standard of living of pancreatic cancer p...
Pancreatic cancer is the fourth leading cause of cancer-related deaths in the United States, and 95% of these cases are caused by PDAC (pancreatic ductal adenocarcinoma). Ketone bodies have previously been shown to decrease cell proliferation and cancer-induced cachexia. The molecular mechanism of ketone body-mediated growth inhibition of pancreati...
Macrophages, apart from being the key effector cells of the innate immune system, also play critical roles during the development and progression of various complex diseases, including cancer. Tumor-associated macrophages, infiltrate tumors during different stages of cancer progression to regulate motility, invasion, and intravasation to metastatic...
Exposing cells to a hypoxic environment leads to significant physiological and molecular alterations. Most of the hypoxic responses are regulated by the transcription factors known as hypoxia-inducible factors (HIFs). HIF1, a heterodimer of hypoxia-stabilized subunit HIF-1alpha and a constitutively expressed subunit HIF-1beta, serves as a key trans...
Most solid tumors are hypoxic in nature due to the limited supply of oxygen to internal tissues. Hypoxia plays an important role in metabolic adaptations of tumors that contribute significantly to cancer pathogenesis. Among the several metabolic alterations induced by hypoxia, hypoxia-mediated increased glucose uptake serves as the hallmark of meta...
(Cancer Cell 32, 71–87; July 10, 2017) In the originally published version of the paper, author Natalie J. Serkova's name was spelled incorrectly as “Sarkova.” The correct spelling of the name is “Serkova,” and the error has been corrected in the original article online. The authors apologize for this error.
Pancreatic cancer cells overexpressing MUC1 rely on aerobic glycolysis and, correspondingly, are dependent on glucose for survival. Our NMR metabolomics comparative analysis of control (S2-013.Neo) and MUC1-overexpressing (S2-013.MUC1) cells demonstrate that MUC1 reprograms glutamine metabolism upon glucose limitation. The observed alteration in gl...
Pancreatic adenocarcinoma is moderately responsive to gemcitabine-based chemotherapy, the most widely used single agent therapy for pancreatic cancer. While the prognosis in pancreatic cancer remains grim in part due to poor response to therapy, previous attempts at identifying and targeting the resistance mechanisms have not been very successful....
Purpose: MUC1, an oncogene overexpressed in multiple solid tumors including pancreatic cancer, reduces overall survival and imparts resistance to radiation and chemotherapies. We previously identified that MUC1 facilitates growth promoting metabolic alterations in pancreatic cancer cells. The present study investigates the role of MUC1-mediated met...
Poor response to cancer therapy due to resistance remains a clinical challenge. The present study establishes a widely prevalent mechanism of resistance to gemcitabine in pancreatic cancer, whereby increased glycolytic flux leads to glucose addiction in cancer cells and a corresponding increase in pyrimidine biosynthesis to enhance the intrinsic le...
Epithelial-cell derived tumors exhibit the Warburg effect that is characterized by an increased rate of glycolysis and lactate release, as well as, reduced oxidative metabolism. It is known that these metabolic alterations of cancer cells result in a tumor microenvironment with a lower pH than that of the plasma. However, little is known regarding...
Pancreatic ductal adenocarcinoma is the fourth leading cause of cancer related deaths in the United States. Due to early metastasis by the time it is diagnosed it advances to advanced stages and becomes unresectable. Oncogene mediated metabolic reprogramming has been shown to promote the growth, maintenance and metastasis of tumors in pancreatic du...
Pancreatic cancer has the lowest survival rate of six perecent among all the cancers in the US and is projected to be the second leading cause of cancer related deaths in a decade. Radiation therapy provides only marginal increases in the survival rate in pancreatic cancer, due to poor responsiveness of pancreatic tumors. Clinical trials indicate a...
Cancer-associated cachexia is a complex metabolic syndrome which leads to excessive loss of skeletal muscle and adipose deposits. Up to 80% of pancreatic cancer patients suffer from cachexia and nearly one third die due to complexities related to the syndrome. Treatment of cachexia will not only improve the standard of living of pancreatic cancer p...
The increased rate of glycolysis and reduced oxidative metabolism are the principal biochemical phenotypes observed in pancreatic ductal adenocarcinoma (PDAC) that lead to the development of an acidic tumor microenvironment. The pH of most epithelial cell-derived tumors is reported to be lower than that of plasma. However, little is known regarding...
Proceedings: AACR 107th Annual Meeting 2016; April 16-20, 2016; New Orleans, LA
Cancer cachexia is a systemic syndrome characterized by progressive weight loss of the patient due to muscle wasting and fat depletion with or without anorexia. About 80% of pancreatic ductal adenocarcinoma (PDAC) patients exhibits cachectic phenotype and it significan...
The objective of this study was to design GE11 peptide (YHWYGYTPQNVI) linked micelles of poly(ethyleneglycol)-block-poly(2-methyl-2-carboxyl-propylenecarbonate-graft-gemcitabine-graft-dodecanol (PEG-b-PCC-g-GEM-g-DC) for enhanced stability and target specificity of gemcitabine (GEM) to EGFR positive pancreatic cancer cells. GE11-PEG-PCD/mPEG-b-PCC-...
Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related deaths in the US. Cancer-associated cachexia is present in up to 80% of PDAC patients and is associated with aggressive disease and poor prognosis. In the present studies we evaluated an anti-cancer natural product silibinin for its effectiveness in targeting panc...
The transcriptional co-activator Yes-associated protein, YAP, is a main effector in the Hippo tumor suppressor pathway. We recently defined a mechanism for positive regulation of YAP through CDK1-mediated mitotic phosphorylation. Here, we show that active YAP promotes pancreatic cancer cell migration, invasion and anchorage-independent growth in a...
The Indian spice turmeric, in which the active and dominant biomolecule is curcumin, has been demonstrated to have significant medicinal properties, including anti-inflammatory and anti-neoplastic effects. This promise is potentially very applicable to musculoskeletal disorders, which are common causes of physician visits worldwide. Research at the...
Overexpression of MUC1 promotes growth promoting metabolic alterations in pancreatic cancer cells. We investigated the role played by MUC1-mediated metabolic alterations in radiation response of pancreatic cancer cells. Our findings indicate that cell survival and clonogenicity of pancreatic cancer cells upon radiation treatment correlate with MUC1...
MUC16, a transmembrane mucin, facilitates pancreatic adenocarcinoma progression and metastasis. In the current studies, we observed that MUC16 knockdown pancreatic cancer cells exhibit reduced glucose uptake and lactate secretion along with reduced migration and invasion potential, which can be restored by supplementing the culture media with lacta...
The HBx oncoprotein of hepatitis B virus has been implicated in the development and progression of hepatocellular carcinoma (HCC). HBx engages multiple signalling and growth-promoting pathways to induce cell proliferation and enhance ribosome biogenesis. Interestingly, the levels of Upstream Binding Factor (UBF) required for rDNA transcription and...
Cancer associated cachexia is a complex metabolic syndrome characterized by excessive loss of skeletal muscle and adipose tissue. Cancer-induced cachexia accounts for nearly 20% of all cancer-related deaths and is most prevalent in patients with gastric, pancreatic, colon and lung cancer. More than 80% pancreatic cancer patients exhibit cachectic p...
Background
Aberrant energy metabolism is a hallmark of cancer. To fulfill the increased energy requirements, tumor cells secrete cytokines/factors inducing muscle and fat degradation in cancer patients, a condition known as cancer cachexia. It accounts for nearly 20% of all cancer-related deaths. However, the mechanistic basis of cancer cachexia an...
Cachexia, a metabolic syndrome, leads to loss of muscle weight and fat tissues. Cancer-induced cachexia accounts for nearly 20% of all cancer-related deaths and is most prevalent in patients with gastric, pancreatic, colon and lung cancer. Although association of cachexia with various types of cancers has been known for a long time, the molecular m...
Nucleolus is a stress sensor associated with cell cycle progression and a viral target. However, the role of nucleolus during hepatitis B virus infection is not studied. Here we show that under nucleolar stress, the HBx oncoprotein down-regulates p53 and p21(Waf1) levels by disrupting the interaction between ribosomal protein L11 and MDM2. Further,...
