Papers by Bal Krishna Chaube
Interestingly, inhibition of either LDH or complex I alone does not induce apoptosis, whereas inh... more Interestingly, inhibition of either LDH or complex I alone does not induce apoptosis, whereas inhibiting both together causes depletion in cellular ATP pool resulting in metabolic catastrophe induced apoptosis. Overall, our study suggests that LDH and complex I play distinct roles in regulating glycolysis and cell proliferation. Inhibition of these two augments synthetic lethality in melanoma.
Molecular Cancer, Sep 1, 2014
Background: Despite modern advances in treatment, skin cancer is still one of the most common cau... more Background: Despite modern advances in treatment, skin cancer is still one of the most common causes of death in the western countries. Chemotherapy plays an important role in melanoma management. Tamoxifen has been used either alone or in-combination with other chemotherapeutic agents to treat melanoma. However, response rate of tamoxifen as a single agent has been comparatively low. In the present study, we investigated whether treatment with methyl-β-cyclodextrin (MCD), a cholesterol depleting agent, increases the efficacy of tamoxifen in melanoma cells. Methods: This was a two-part study that incorporated in vitro effects of tamoxifen and MCD combination by analyzing cell survival, apoptosis and cell cycle analysis and in vivo antitumor efficacy on tumor isografts in C57BL/6J mice. Results: MCD potentiated tamoxifen induced anticancer effects by causing cell cycle arrest and induction of apoptosis. Sensitization to tamoxifen was associated with down regulation of antiapoptotic protein Bcl-2 , up-regulation of proapoptotic protein Bax, reduced caveolin-1 (Cav-1) and decreased pAkt/pERK levels. Co-administration of tamoxifen and MCD caused significant reduction in tumor volume and tumor weight in mice due to enhancement of drug uptake in the tumor. Supplementation with cholesterol abrogated combined effect of tamoxifen and MCD. Conclusion: Our results emphasize a potential synergistic effect of tamoxifen with MCD, and therefore, may provide a unique therapeutic window for improvement in melanoma treatment.
Loss of cis-PTase function in the liver promotes a highly penetrant form of fatty liver disease that rapidly transitions to hepatocellular carcinoma
Obesity-linked fatty liver is a significant risk factor for hepatocellular carcinoma (HCC)1,2; ho... more Obesity-linked fatty liver is a significant risk factor for hepatocellular carcinoma (HCC)1,2; however, the molecular mechanisms underlying the transition from non-alcoholic fatty liver disease (NAFLD) to HCC remains unclear. The present study explores the role of the endoplasmic reticulum (ER)-associated protein NgBR, an essential component of the cis-prenyltransferases (cis-PTase) enzyme3, in chronic liver disease. Here we show that genetic depletion of NgBR in hepatocytes of mice (N-LKO) intensifies triacylglycerol (TAG) accumulation, inflammatory responses, ER/oxidative stress, and liver fibrosis, ultimately resulting in HCC development with 100% penetrance after four months on a high-fat diet. Comprehensive genomic and single cell transcriptomic atlas from affected livers provides a detailed molecular analysis of the transition from liver pathophysiology to HCC development. Importantly, pharmacological inhibition of diacylglycerol acyltransferase-2 (DGAT2), a key enzyme in hepa...
Editorial: Cancer metabolism: molecular insights, metabolic crosstalk in the tumor microenvironment, and implications for therapy
Frontiers in Oncology
Cell Death & Disease, 2015
Inaccessibility of drugs to poorly vascularized strata of tumor is one of the limiting factors in... more Inaccessibility of drugs to poorly vascularized strata of tumor is one of the limiting factors in cancer therapy. With the advent of bystander effect (BE), it is possible to perpetuate the cellular damage from drug-exposed cells to the unexposed ones. However, the role of infiltrating tumor-associated macrophages (TAMs), an integral part of the tumor microenvironment, in further intensifying BE remains obscure. In the present study, we evaluated the effect of mitomycin C (MMC), a chemotherapeutic drug, to induce BE in cervical carcinoma. By using cervical cancer cells and differentiated macrophages, we demonstrate that MMC induces the expression of FasL via upregulation of PPARγ in both cell types (effector cells) in vitro, but it failed to induce bystander killing in cervical cancer cells. This effect was primarily owing to the proteasomal degradation of death receptors in the cervical cancer cells. Pre-treatment of cervical cancer cells with MG132, a proteasomal inhibitor, facilit...
Additional file 8: Figure S6. of Weight control interventions improve therapeutic efficacy of dacarbazine in melanoma by reversing obesity-induced drug resistance
Effect of inhibiting FASN, Cav-1, and P-gp on response of B16F1 cells to DTIC upon culture in CM ... more Effect of inhibiting FASN, Cav-1, and P-gp on response of B16F1 cells to DTIC upon culture in CM collected from 3T3-L1 cells. 3T3-L1 cells were induced to differentiate with 500 μM 3-isobutyl-1-methylxanthine (IBMX) and 250 μM dexamethasone (DEX). The medium was changed every alternate day. After 10 days, cells were washed twice with DMEM and fresh DMEM without serum was added to the cells. After 18 h, conditioned medium (CM) was collected from undifferentiated or differentiated 3T3-L1 cells. Thereafter, B16F10 or B16F1 cells were cultured in these CM for 48 h. First, cells were treated with respective inhibitors followed by treatment of DTIC for 48 h. Then, the medium was changed and fresh medium was added. The medium was changed every 2–3 days. After 10 days, the cells were stained with 0.05% crystal violet and images were taken using Olympus digital camera. Data were quantitated using ImageJ software. The data are representative of experiments performed three times; PA = preadipo...
Additional file 5: Figure S3. of Weight control interventions improve therapeutic efficacy of dacarbazine in melanoma by reversing obesity-induced drug resistance
Effect of inhibition of FASN, Cav-1, and P-gp on response of B16F1 cells to DTIC. B16F1 cells wer... more Effect of inhibition of FASN, Cav-1, and P-gp on response of B16F1 cells to DTIC. B16F1 cells were chronically grown in medium containing 5% serum collected from experimental ND or HFD C57BL/6J mice for 15 days. Thereafter, these cells were subjected to long-term survival assay. First, cells were treated with respective inhibitors followed by treatment of DTIC for 48 h. Then, the medium was changed and fresh medium was added. The medium was changed every 2–3 days. After 10 days, the cells were stained with 0.05% crystal violet and images were taken using Olympus digital camera. Data were quantitated using ImageJ software. The data are representative of experiments performed three times; Ceru or C = cerulenin; MCD or M = methyl β-cyclodextrin; Vera or V = verapamil. The results are given as means ± standard deviation; *, p
Additional file 2: Table S2. of Weight control interventions improve therapeutic efficacy of dacarbazine in melanoma by reversing obesity-induced drug resistance
Obesity-associated parameters in the experimental ND mice recorded at the end of the experiment. ... more Obesity-associated parameters in the experimental ND mice recorded at the end of the experiment. ND male C57BL/6J mice were divided into two major groups. One group was orally treated with orlistat every alternate day before inoculating with B16F10 cells. The second group was orally given vehicle control on every alternate day for 8 weeks. Mice from both the groups (N = 11 per each group) were injected (s.c.) with B16F10 cells (2 × 105 cells/mouse in 100 μl PBS). After tumor formation, vehicle or DTIC treatment was given as per the experimental layout shown in Figure 1. Their body weight was monitored weekly throughout the study, and serum was collected at the end of the experiment. Blood glucose, serum TG, serum cholesterol, serum-free fatty acids, and serum LDLc were measured. Serum factors including leptin, adiponectin, insulin, resistin, IL-6, and TNF-α were estimated by ELISA. The results are given as means ± standard deviation. (PDF 113 kb)
Additional file 7: Figure S5. of Weight control interventions improve therapeutic efficacy of dacarbazine in melanoma by reversing obesity-induced drug resistance
Effect of adipocyte-secreted factors on Rh-123 efflux in B16F1 cells. 3T3-L1 cells were induced t... more Effect of adipocyte-secreted factors on Rh-123 efflux in B16F1 cells. 3T3-L1 cells were induced to differentiate with 500 μM 3-isobutyl-1-methylxanthine (IBMX) and 250 μM dexamethasone (DEX). The medium was changed every alternate day. After 10 days, cells were washed twice with DMEM and fresh DMEM without serum was added to the cells. After 18 h, conditioned medium (CM) was collected from undifferentiated or differentiated 3T3-L1 cells. Thereafter, B16F10 or B16F1 cells were cultured in these CM for 48 h. Further, these cells were subjected to Rh-123 efflux assay. Data were acquired on FACS Calibur and analyzed using BD CellQuest Pro software. The data are representative of experiments performed three times; PA = preadipocytes; ID = differentiated 3T3-L1 cells induced by IBMX and DEX; Vera = verapamil. (PDF 150 kb)
Additional file 1: of Elevated circulatory levels of leptin and resistin impair therapeutic efficacy of dacarbazine in melanoma under obese state
Figure S1. Validation of immunodepletion of leptin form serum collected from HFD C57BL/6J mice. F... more Figure S1. Validation of immunodepletion of leptin form serum collected from HFD C57BL/6J mice. Figure S2. A375 cells were cultured in the presence of leptin or resistin along with inhibitors for 48Ă‚ h. Table S1. Evaluation of obesity-associated factors in WT and db/db mice. Table S2. Evaluation of obesity-associated factors in WT and db/db mice. (DOC 319 kb)
Breast and hepatocellular carcinoma (HCC) are the second and fifth most prevalent cancers respect... more Breast and hepatocellular carcinoma (HCC) are the second and fifth most prevalent cancers respectively, and leading causes of cancer associated deaths in the entire world1–3. Although surgical removal of tumor is still the primary treatment of choice, apart from surgery or radiotherapy, chemotherapy remains to be most efficient way for preventing cancer cell growth and metastasis thereby enhancing the survival of cancer patients4. One of the major limitations of chemotherapeutic drugs is toxicity due to high dose regimen or improper efficacy of drugs towards tumor cells5. Therefore, new strategies to achieve favorable response to chemotherapy for improvement in the prognosis of breast and liver cancer are urgently desirable. Doxorubicin (DOX), an anthracycline antibiotic, is one of the most effective and widely used chemotherapeutic agents for the treatment of various malignancies including breast and liver for the past twenty years6. However, the common drawbacks in the clinical us...
Heterotopic model of Lewis lung cancer (LLC) and orthotopic B16 mouse melanoma were used. For ort... more Heterotopic model of Lewis lung cancer (LLC) and orthotopic B16 mouse melanoma were used. For orthotopic model of lung cancer LL/2 Red-Fluc cells (Perkin Elmer, Hopkinton, MA) were used. LLC (LL/2 (LLC1-ATCC CRL-1642) and B16 (B16-F0-ATCC CRL-6322) cells were grown exponentially. 10 6 cells were injected subcutaneously into the dorsal flank of 8-10-week-old mice as described (1). When tumors became palpable, they were monitored for growth by measuring the length and width of the tumor using a caliper, and tumor volume was determined by the following formula: volume = 0.52Ă—(width) 2 Ă—(length). Mice with no palpable mass at day 8 were removed from the study.
Weight control interventions reverse diet-induced obesity impaired therapeutic response of melanoma to dacarbazine
Cancer and Metabolism, 2016
Journal of Clinical Investigation
(YS). activity was associated with decreased plasma HDL-C under physiological conditions. However... more (YS). activity was associated with decreased plasma HDL-C under physiological conditions. However, this relationship was not apparent in pathophysiological situations, such as obesity and diabetes; thus, further mechanistic investigation is needed to elucidate the relationship between HL and HDL-C under lipid overload conditions. Methods Detailed information on experimental procedures and reagents is provided in Supplemental Methods.
Metformin induced lactic acidosis impaired response of cancer cells towards paclitaxel and doxorubicin: Role of monocarboxylate transporter
Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease
ABSTRACTAngiopoietin-like 4 (ANGPTL4) is a major regulator of lipoprotein lipase (LPL) activity, ... more ABSTRACTAngiopoietin-like 4 (ANGPTL4) is a major regulator of lipoprotein lipase (LPL) activity, which is responsible for maintaining optimal levels of circulating triacylglycerol (TAG) for distribution to different tissues including the adipose tissues (ATs), heart, muscle and liver. Dysregulation of trafficking and portioning of fatty acids (FA) can promote ectopic lipid accumulation in metabolic tissues such as the liver, ultimately leading to systemic metabolic dysfunction. To investigate how ANGPTL4 regulates hepatic lipid and glucose metabolism, we generated liver-specific ANGPTL4 knockout mice (LKO). Using metabolic turnover studies, we demonstrate that hepatic ANGPTL4 deficiency facilitates catabolism of TAG-rich lipoprotein (TRL) remnants in the liver via increased hepatic lipase (HL) activity, which results in a significant reduction in circulating TAG and cholesterol levels. Deletion of hepatocyte ANGPTL4 protects against diet-induce obesity, glucose intolerance, liver st...
Journal of Clinical Investigation
Conflict of interest: DLR is a cofounder of, consultant for, and stockholder in HistoRx, the excl... more Conflict of interest: DLR is a cofounder of, consultant for, and stockholder in HistoRx, the exclusive license of the Yale-owned AQUA technology. YKR is a founder of pHLIP Inc., with shares in the company.
Cancer & metabolism, 2018
Obesity is associated with increased risk, poor prognosis and outcome of therapy, in various canc... more Obesity is associated with increased risk, poor prognosis and outcome of therapy, in various cancers. Obesity-associated factors or adipokines, especially leptin and resistin, are purported to promote growth, survival, proliferation, and invasiveness of cancer cells. However, the mechanistic link between these adipokines and therapeutic response in malignancies is not clearly understood. ob/ob and db/db mouse models were used in this study to evaluate the role of leptin and resistin towards the outcome of dacarbazine (DTIC) therapy in melanoma. Unique in vitro approaches were employed to complement in vivo findings by culturing melanoma cells in the serum collected from the experimental mice. Here, we have shown the role of important adipokines leptin and resistin in growth and the outcome of DTIC therapy in melanoma. Both leptin and resistin not only enhance proliferation of melanoma cells but also are involved in impairing the therapeutic efficacy of DTIC. Leptin and resistin trea...
Molecular metabolism, Jan 29, 2018
Brown adipose tissue (BAT) controls triglyceride-rich lipoprotein (TRL) catabolism. This process ... more Brown adipose tissue (BAT) controls triglyceride-rich lipoprotein (TRL) catabolism. This process is mediated by the lipoprotein lipase (LPL), an enzyme that catalyzed the hydrolysis of triglyceride (TAG) in glycerol and fatty acids (FA), which are burned to generate heat. LPL activity is regulated by angiopoietin-like 4 (ANGPTL4), a secretory protein produced in adipose tissues (AT), liver, kidney, and muscle. While the role of ANGPTL4 in regulating lipoprotein metabolism is well established, the specific contribution of BAT derived ANGPTL4 in controlling lipid and glucose homeostasis is not well understood. We generated a novel mouse model lacking ANGPTL4 specifically in brown adipose tissue (BAT-KO). Here, we report that specific deletion of ANGPTL4 in BAT results in enhanced LPL activity, circulating TAG clearance and thermogenesis. Absence of ANGPTL4 in BAT increased FA oxidation and reduced FA synthesis. Importantly, we observed that absence of ANGPTL4 in BAT leads to a remarka...
JCI insight, Jan 22, 2018
Alterations in ectopic lipid deposition and circulating lipids are major risk factors for develop... more Alterations in ectopic lipid deposition and circulating lipids are major risk factors for developing cardiometabolic diseases. Angiopoietin-like protein 4 (ANGPTL4), a protein that inhibits lipoprotein lipase (LPL), controls fatty acid (FA) uptake in adipose and oxidative tissues and regulates circulating triacylglycerol-rich (TAG-rich) lipoproteins. Unfortunately, global depletion of ANGPTL4 results in severe metabolic abnormalities, inflammation, and fibrosis when mice are fed a high-fat diet (HFD), limiting our understanding of the contribution of ANGPTL4 in metabolic disorders. Here, we demonstrate that genetic ablation of ANGPTL4 in adipose tissue (AT) results in enhanced LPL activity, rapid clearance of circulating TAGs, increased AT lipolysis and FA oxidation, and decreased FA synthesis in AT. Most importantly, we found that absence of ANGPTL4 in AT prevents excessive ectopic lipid deposition in the liver and muscle, reducing novel PKC (nPKC) membrane translocation and enhanc...
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Papers by Bal Krishna Chaube