The Warburg effect in human pancreatic cancer cells triggers cachexia in athymic mice carrying the cancer cells

Abstract Background Gemcitabine (GEM) resistance remains a significant clinical challenge in pancreatic cancer treatment. Here, we investigated the therapeutic utility of everolimus (Evr), an inhibitor of mammalian target of rapamycin (mTOR), in targeting the Warburg effect to overcome GEM resistance in pancreatic cancer. Methods The effect of Evr and/or mTOR overexpression or GEM on cell viability, migration, apoptosis, and glucose metabolism (Warburg effect) was evaluated in GEM-sensitive (GEMsen) and GEM-resistant (GEMres) pancreatic cancer cells. Results We demonstrated that the upregulation of mTOR enhanced cell viability and favored the Warburg effect in pancreatic cancer cells via the regulation of PI3K/AKT/mTOR signaling. However, this effect was counteracted by Evr, which inhibited aerobic glycolysis by reducing the levels of glucose, lactic acid, and adenosine triphosphate and suppressing the expression of glucose transporter 1, lactate dehydrogenase-B, hexokinase 2, and pyruvate kinase M2 in GEMsen and GEMres cells. Evr also promoted apoptosis by upregulating the pro-apoptotic proteins Bax and cytochrome-c and downregulating the anti-apoptotic protein Bcl-2. GEM was minimally effective in suppressing GEMres cell activity, but the therapeutic effectiveness of Evr against pancreatic cancer growth was greater in GEMres cells than that in GEMsen cells. In vivo studies confirmed that while GEM failed to inhibit the progression of GEMres tumors, Evr significantly decreased the volume of GEMres tumors while suppressing tumor cell proliferation and enhancing tumor apoptosis in the presence of GEM. Conclusions Evr treatment may be a promising strategy to target the growth and activity of GEM-resistant pancreatic cancer cells by regulating glucose metabolism via inactivation of PI3K/AKT/mTOR signaling.

Download Full-text

The Plasma Membrane Calcium Pump in Pancreatic Cancer Cells Exhibiting the Warburg Effect Relies on Glycolytic ATP

Journal of Biological Chemistry ◽

10.1074/jbc.m115.668707 ◽

2015 ◽

Vol 290 (41) ◽

pp. 24760-24771 ◽

Cited By ~ 20

Author(s):

Andrew D. James ◽

Waseema Patel ◽

Zohra Butt ◽

Magretta Adiamah ◽

Raga Dakhel ◽

...

Keyword(s):

Pancreatic Cancer ◽

Plasma Membrane ◽

Cancer Cells ◽

Warburg Effect ◽

Calcium Pump ◽

Pancreatic Cancer Cells ◽

Plasma Membrane Calcium Pump ◽

Glycolytic Atp ◽

The Warburg Effect

Download Full-text

In Vitro and In Vivo Antitumor Efficacy of Docetaxel and Sorafenib Combination in Human Pancreatic Cancer Cells

Current Cancer Drug Targets ◽

10.2174/1568210204916170096 ◽

2010 ◽

Vol 999 (999) ◽

pp. 1-11

Author(s):

P. Ulivi ◽

C. Arienti ◽

W. Zoli ◽

M. Scarsella ◽

S. Carloni ◽

...

Keyword(s):

Pancreatic Cancer ◽

Cancer Cells ◽

Antitumor Efficacy ◽

Human Pancreatic Cancer ◽

Pancreatic Cancer Cells

Download Full-text

Effect of Low Molecular Weight Heparins and Fondaparinux Upon Thrombin Generation Triggered by Human Pancreatic Cancer Cells BXPC3

Current Vascular Pharmacology ◽

10.2174/157016111206141210121441 ◽

2014 ◽

Vol 12 (6) ◽

pp. 893-902 ◽

Cited By ~ 5

Author(s):

Grigoris Gerotziafas ◽

Vassiliki Galea ◽

Elisabeth Mbemba ◽

Mouna Sassi ◽

Marie-Paule Roman ◽

...

Keyword(s):

Pancreatic Cancer ◽

Molecular Weight ◽

Cancer Cells ◽

Thrombin Generation ◽

Human Pancreatic Cancer ◽

Low Molecular Weight ◽

Low Molecular Weight Heparins ◽

Pancreatic Cancer Cells

Download Full-text

Cyathus striatus Extract Induces Apoptosis in Human Pancreatic Cancer Cells and Inhibits Xenograft Tumor Growth In Vivo

Cancers ◽

10.3390/cancers13092017 ◽

2021 ◽

Vol 13 (9) ◽

pp. 2017

Author(s):

Lital Sharvit ◽

Rinat Bar-Shalom ◽

Naiel Azzam ◽

Yaniv Yechiel ◽

Solomon Wasser ◽

...

Keyword(s):

Pancreatic Cancer ◽

Cancer Cells ◽

Pancreatic Cancer Cell Line ◽

Cancer Cell Line ◽

Culture Liquid ◽

Human Pancreatic Cancer ◽

P53 Signaling ◽

Pancreatic Cancer Cells

Pancreatic cancer is a highly lethal disease with limited options for effective therapy and the lowest survival rate of all cancer forms. Therefore, a new, effective strategy for cancer treatment is in need. Previously, we found that a culture liquid extract of Cyathus striatus (CS) has a potent antitumor activity. In the present study, we aimed to investigate the effects of Cyathus striatus extract (CSE) on the growth of pancreatic cancer cells, both in vitro and in vivo. The proliferation assay (XTT), cell cycle analysis, Annexin/PI staining and TUNEL assay confirmed the inhibition of cell growth and induction of apoptosis by CSE. A Western blot analysis demonstrated the involvement of both the extrinsic and intrinsic apoptosis pathways. In addition, a RNAseq analysis revealed the involvement of the MAPK and P53 signaling pathways and pointed toward endoplasmic reticulum stress induced apoptosis. The anticancer activity of the CSE was also demonstrated in mice harboring pancreatic cancer cell line-derived tumor xenografts when CSE was given for 5 weeks by weekly IV injections. Our findings suggest that CSE could potentially be useful as a new strategy for treating pancreatic cancer.

Download Full-text

Patterns and Relevance of Langerhans Islet Invasion in Pancreatic Cancer

Cancers ◽

10.3390/cancers13020249 ◽

2021 ◽

Vol 13 (2) ◽

pp. 249

Author(s):

Ruediger Goess ◽

Ayse Ceren Mutgan ◽

Umut Çalışan ◽

Yusuf Ceyhun Erdoğan ◽

Lei Ren ◽

...

Keyword(s):

Diabetes Mellitus ◽

Pancreatic Cancer ◽

Cancer Cells ◽

Tumor Cells ◽

Islet Cells ◽

Human Pancreatic Cancer ◽

Type I ◽

Type Iv ◽

Pancreatic Cancer Cells

Background: Pancreatic cancer‐associated diabetes mellitus (PC‐DM) is present in most patients with pancreatic cancer, but its pathogenesis remains poorly understood. Therefore, we aimed to characterize tumor infiltration in Langerhans islets in pancreatic cancer and determine its clinical relevance. Methods: Langerhans islet invasion was systematically analyzed in 68 patientswith pancreatic ductal adenocarcinoma (PDAC) using histopathological examination and 3D in vitro migration assays were performed to assess chemoattraction of pancreatic cancer cells to isletcells. Results: Langerhans islet invasion was present in all patients. We found four different patterns of islet invasion: (Type I) peri‐insular invasion with tumor cells directly touching the boundary, but not penetrating the islet; (Type II) endo‐insular invasion with tumor cells inside the round islet; (Type III) distorted islet structure with complete loss of the round islet morphology; and (Type IV)adjacent cancer and islet cells with solitary islet cells encountered adjacent to cancer cells. Pancreatic cancer cells did not exhibit any chemoattraction to islet cells in 3D assays in vitro. Further, there was no clinical correlation of islet invasion using the novel Islet Invasion Severity Score (IISS), which includes all invasion patterns with the occurrence of diabetes mellitus. However, Type IV islet invasion was related to worsened overall survival in our cohort. Conclusions: We systematically analyzed, for the first time, islet invasion in human pancreatic cancer. Four different main patterns of islet invasion were identified. Diabetes mellitus was not related to islet invasion. However, moreresearch on this prevailing feature of pancreatic cancer is needed to better understand underlying principles.

Download Full-text