Expression of SGLT1, Bcl-2 and p53 in Primary Pancreatic Cancer Related to Survival

Casneuf, Veerle; Fonteyne, Philippe; Damme, Nancy Van; Demetter, Pieter; Pauwels, Patrick; Hemptinne, Bernard de; Vos, Martine De; Wiele, Christophe Van de; Peeters, Marc

doi:10.1080/07357900801956363

Cited by 65 publications

(63 citation statements)

References 24 publications

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“…The low luminal glucose concentrations provide some protection against luminal bacterial growth and genetic or pharmacological inhibition of the carriers may favor the development of urinary tract infection [14, 15] and diarrhea [16, 17]. SGLT1 expression is, however, not restricted to renal and intestinal epithelia [18], but has also been observed in heart [18, 19], lung [18], liver [18], tumor cells [20-27] and lymphocytes [28]. The expression of SGLT1 in lymphocytes prompted us to speculate that SGLT1 expression could modulate immune function during bacterial infection.…”

Section: Introductionmentioning

confidence: 99%

SGLT1 Deficiency Turns Listeria Infection into a Lethal Disease in Mice

Sharma

Khairnar

Madunić

et al. 2017

Cell Physiol Biochem

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Background: Cellular glucose uptake may involve either non-concentrative glucose carriers of the GLUT family or Na⁺-coupled glucose-carrier SGLT1, which accumulates glucose against glucose gradients and may thus accomplish cellular glucose uptake even at dramatically decreased extracellular glucose concentrations. SGLT1 is not only expressed in epithelia but as well in tumour cells and immune cells. Immune cell functions strongly depend on their metabolism, therefore we hypothesized that deficiency of SGLT1 modulates the defence against bacterial infection. To test this hypothesis, we infected wild type mice and gene targeted mice lacking functional SGLT1 with Listeria monocytogenes. Methods: SGLT1 deficient mice and wild type littermates were infected with 1x10⁴ CFU Listeria monocytogenes intravenously. Bacterial titers were determined by colony forming assay, SGLT1, TNF-α, IL-6 and IL-12a transcript levels were determined by qRT-PCR, as well as SGLT1 protein abundance and localization by immunohistochemistry. Results: Genetic knockout of SGLT1 (Slc5a1^–/– mice) significantly compromised bacterial clearance following Listeria monocytogenes infection with significantly enhanced bacterial load in liver, spleen, kidney and lung, and significantly augmented hepatic expression of TNF-α and IL-12a. While all wild type mice survived, all SGLT1 deficient mice died from the infection. Conclusions: SGLT1 is required for bacterial clearance and host survival following murine Listeria infection.

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Section: Introductionmentioning

confidence: 99%

SGLT1 Deficiency Turns Listeria Infection into a Lethal Disease in Mice

Sharma

Khairnar

Madunić

et al. 2017

Cell Physiol Biochem

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“…The death-life rheostat is mediated, at least in part, by competitive dimerization between selective pairs of antagonists and agonists [15,16]. Furthermore, diverse effects of P53 on the transcription of the Bcl-2 protein family that regulate apoptosis substantially affect the biological aggressiveness of PADC [17,18]. The transcription of Bax, a proapoptotic member of the Bcl-2 family, is activated by wild-type P53, while Bcl-2, which functions to prevent apoptosis, is transcriptionally repressed by wild-type P53 [19,20].…”

Section: Introductionmentioning

confidence: 99%

Apoptosis and Expression of the Bcl-2 Family of Proteins and P53 in Human Pancreatic Ductal Adenocarcinoma

Chen¹,

Zheng²,

Kang

et al. 2011

Med Princ Pract

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Objective: The purpose of this study was to clarify the association between P53 and the Bcl-2 family (Bcl-2, Bax, Bcl-xL, Bcl-xS) expression and apoptosis in pancreatic ductal adenocarcinoma (PDAC). Subjects and Methods: A total of 70 patients with PDAC were studied. The expression of P53 protein in PDAC was assessed using the immunohistochemical method, which categorized the PDAC patients into two groups: group 1: 36 cases with immunonegative P53(–), and group 2: 34 cases with immunopositive P53(+). The expression of Bcl-2, Bax, Bcl-xL, and Bcl-xS in the 70 PDAC cases was detected by immunohistochemical and Western blotting methods. The apoptotic index (AI) was also measured in these samples by the terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) method. The relation between P53 and the Bcl-2 protein family and apoptosis was then evaluated. Results: Bcl-2 and Bcl-xS expression was significantly associated with P53 (p < 0.05). No clear associations were found among P53, Bax and Bcl-xL expression (p > 0.05). The AI of groups 1 and 2 was 12.1 ± 2.47 and 8.1 ± 1.48, respectively (p = 0.023). There was no relationship between AI and Bcl-2, Bax, Bcl-xL and Bcl-xS expression (p > 0.05, respectively). Bcl-2/Bax ratio was significantly associated with AI (p < 0.01). Conclusion: Bcl-2 and Bcl-xS represent significant anti- and proapoptotic proteins, respectively, modulated through a P53-dependent pathway in PDAC, and P53 modulated apoptosis mainly through Bcl-2/Bax ratio.

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“…SGLT1 is, however, in addition expressed in a variety of tumor cells [20][21][22][23][24][25][26][27]. Similar to activated lymphocytes [75,[85][86][87], tumor cells further express the facilitative glucose transporter GLUT1 [76,77].…”

Section: Discussionmentioning

confidence: 99%

“…SGLT1 and its isoform SGLT2 are expressed in epithelial cells and accomplish the concentrative cellular uptake of glucose from the intestinal or renal tubular lumen across the apical cell membrane [19]. SGLT1 is further expressed in a wide variety of tumor cells [20][21][22][23][24][25][26][27]. Tumor cells meet their need for energy mainly by glycolysis [22,[28][29][30][31].…”

Section: Introductionmentioning

confidence: 99%

Expression of JAK3 Sensitive Na+ Coupled Glucose Carrier SGLT1 in Activated Cytotoxic T Lymphocytes

Bhavsar

Singh

Sharma

et al. 2016

Cell Physiol Biochem

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Background: Similar to tumor cells, activated T-lymphocytes generate ATP mainly by glycolytic degradation of glucose. Lymphocyte glucose uptake involves non-concentrative glucose carriers of the GLUT family. In contrast to GLUT isoforms, Na⁺-coupled glucose-carrier SGLT1 accumulates glucose against glucose gradients and is effective at low extracellular glucose concentrations. The present study explored expression and regulation of SGLT1 in activated murine splenic cytotoxic T cells (CTLs) and human Jurkat T cells. Methods: FACS analysis, immunofluorescence, confocal microscopy, chemiluminescence and Western blotting were employed to estimate SGLT1 expression, function and regulation in lymphocytes, as well as dual electrode voltage clamp in SGLT1 ± JAK3 expressing Xenopus oocytes to quantify the effect of janus kinase3 (JAK3) on SGLT1 function. Results: SGLT1 is expressed in murine CTLs and also in human Jurkat T cells. 2-(N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino)-2-deoxyglucose uptake was significantly decreased by SGLT1-blocker phloridzin (0.2 mM) and by pharmacological inhibition of JAK3 with WHI-P131 (156 µM), WHI-P154 (11.2 µM) and JAK3 inhibitor VI (0.5 µM). Electrogenic glucose transport (I_glucose) in Xenopus oocytes expressing human SGLT1 was increased by additional expression of human wild type JAK3, active ^A568VJAK3 but not inactive ^K851AJAK3. Coexpression of JAK3 enhanced the maximal transport rate without significantly modifying affinity of the carrier. I_glucose in SGLT1+JAK3 expressing oocytes was significantly decreased by WHI-P154 (11.2 µM). JAK3 increased the SGLT1 protein abundance in the cell membrane. Inhibition of carrier insertion by brefeldin A (5 µM) in SGLT1+JAK3 expressing oocytes resulted in a decline of I_glucose, which was similar in presence and absence of JAK3. Conclusions: SGLT1 is expressed in murine cytotoxic T cells and human Jurkat T cells and significantly contributes to glucose uptake in those cells post activation. JAK3 up-regulates SGLT1 activity by increasing the carrier protein abundance in the cell membrane, an effect enforcing cellular glucose uptake into activated lymphocytes and thus contributing to the immune response.

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Expression of SGLT1, Bcl-2 and p53 in Primary Pancreatic Cancer Related to Survival

Cited by 65 publications

References 24 publications

SGLT1 Deficiency Turns Listeria Infection into a Lethal Disease in Mice

SGLT1 Deficiency Turns Listeria Infection into a Lethal Disease in Mice

Apoptosis and Expression of the Bcl-2 Family of Proteins and P53 in Human Pancreatic Ductal Adenocarcinoma

Expression of JAK3 Sensitive Na+ Coupled Glucose Carrier SGLT1 in Activated Cytotoxic T Lymphocytes

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