ZIP4 regulates pancreatic cancer cachexia and post-surgical survival through activation of P38 pathway

Most patients with pancreatic adenocarcinoma (PDAC) suffer cachexia; some do not. To model heterogeneity, we used patient-derived orthotopic xenografts. These phenocopied donor weight loss. Furthermore, muscle wasting correlated with mortality and murine IL-6, and human IL-6 associated with the greatest murine cachexia. In cell culture and mice, PDAC cells elicited adipocyte IL-6 expression and IL-6 plus IL-6 receptor (IL6R) in myocytes and blood. PDAC induced adipocyte lipolysis and muscle steatosis, dysmetabolism, and wasting. Depletion of IL-6 from malignant cells halved adipose wasting and abolished myosteatosis, dysmetabolism, and atrophy. In culture, adipocyte lipolysis required soluble (s)IL6R, while IL-6, sIL6R, or palmitate induced myotube atrophy. PDAC cells activated adipocytes to induce myotube wasting and activated myotubes to induce adipocyte lipolysis. Thus, PDAC cachexia results from tissue crosstalk via a feed-forward, IL-6 trans-signaling loop. Malignant cells signal via IL-6 to muscle and fat, muscle to fat via sIL6R, and fat to muscle via lipids and IL-6, all targetable mechanisms for treatment of cachexia.

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The systemic activin response to pancreatic cancer: Implications for effective cancer cachexia therapy

10.1101/343871 ◽

2018 ◽

Author(s):

Xiaoling Zhong ◽

Marianne Pons ◽

Christophe Poirier ◽

Yanlin Jiang ◽

Jianguo Liu ◽

...

Keyword(s):

Pancreatic Cancer ◽

Weight Loss ◽

Pancreatic Ductal Adenocarcinoma ◽

Conditioned Medium ◽

Tumor Cells ◽

Stromal Cells ◽

Cancer Cachexia ◽

Dominant Negative ◽

Prolonged Survival ◽

Ductal Adenocarcinoma

AbstractPancreatic ductal adenocarcinoma (PDAC) is a particularly lethal malignancy with high rates of cachexia. Serum activin correlates with PDAC cachexia and mortality, while activin administration causes cachexia in mice. We studied activin in human tumors and in mice with orthotopic or genetic PDAC. Cachexia severity correlated with activin expression in tumor lines. Activins were expressed in both cancer and tumor stromal cells, but also in organs in murine PDAC cachexia. Tumor cells expressed activin-βA, or Inhba, while organs expressed both activin-βA and activin-βB, or Inhbb. PDAC elicits activin expression; PDAC conditioned medium induced activin and atrophy of myotubes. Treatment with the activin trap, ACVR2B/Fc, reduced cachexia and prolonged survival in mice with activin-low tumors, and reduced cachexia in activin-high tumors, without affecting activin expression in organs. Mice expressing dominant negative ACVR2B in muscle were protected for weight loss but not survival. Overall our results indicate that PDAC induces a systemic activin response, leading to cachexia, and that activin targets might include organs beyond muscle. Targeting of both tumor-derived and host-derived activins could improve cachexia therapy.

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Emodin and rhein decrease levels of hypoxia-inducible factor-1α in human pancreatic cancer cells and attenuate cancer cachexia in athymic mice carrying these cells

Oncotarget ◽

10.18632/oncotarget.21330 ◽

2017 ◽

Vol 8 (50) ◽

pp. 88008-88020 ◽

Cited By ~ 15

Author(s):

Lijuan Hu ◽

Rui Cui ◽

Hongyi Liu ◽

Feng Wang

Keyword(s):

Pancreatic Cancer ◽

Cancer Cells ◽

Cancer Cachexia ◽

Hypoxia Inducible Factor ◽

Human Pancreatic Cancer ◽

Athymic Mice ◽

Hypoxia Inducible Factor 1Α ◽

Pancreatic Cancer Cells

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Pancreatic Cancer and Cachexia—Metabolic Mechanisms and Novel Insights

Nutrients ◽

10.3390/nu12061543 ◽

2020 ◽

Vol 12 (6) ◽

pp. 1543

Author(s):

Kalliopi Anna Poulia ◽

Panagiotis Sarantis ◽

Dimitra Antoniadou ◽

Evangelos Koustas ◽

Adriana Papadimitropoulou ◽

...

Keyword(s):

Quality Of Life ◽

Pancreatic Cancer ◽

Cancer Cachexia ◽

Clinical Effect ◽

Treatment Algorithm ◽

Host Factors ◽

Surgical Removal ◽

Malignant Diseases ◽

Appropriate Treatment

Cachexia is a major characteristic of multiple non-malignant diseases, advanced and metastatic cancers and it is highly prevalent in pancreatic cancer, affecting almost 70%–80% of the patients. Cancer cachexia is a multifactorial condition accompanied by compromised appetite and changes in body composition, i.e., loss of fat. It is associated with lower effectiveness of treatment, compromised quality of life, and higher mortality. Understanding the complex pathways underlying the pathophysiology of cancer cachexia, new therapeutic targets will be unraveled. The interplay between tumor and host factors, such as cytokines, holds a central role in cachexia pathophysiology. Cytokines are possibly responsible for anorexia, hypermetabolism, muscle proteolysis, and apoptosis. In particular, cachexia in pancreatic cancer might be the result of the surgical removal of pancreas parts. In recent years, many studies have been carried out to identify an effective treatment algorithm for cachexia. Choosing the most appropriate treatment, the clinical effect and the risk of adverse effects should be taken under consideration. The purpose of this review is to highlight the pathophysiological mechanisms as well as the current ways of cachexia treatment in the pharmaceutical and the nutrition field.

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Cucurbitacin D Induces G2/M Phase Arrest and Apoptosis via the ROS/p38 Pathway in Capan-1 Pancreatic Cancer Cell Line

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2020/6571674 ◽

2020 ◽

Vol 2020 ◽

pp. 1-10

Author(s):

Myeong-Sun Kim ◽

Kangwook Lee ◽

Jin Mo Ku ◽

Yu-Jeong Choi ◽

Kyungyul Mok ◽

...

Keyword(s):

Pancreatic Cancer ◽

Cell Line ◽

Cancer Cell ◽

Pancreatic Cancer Cell ◽

Anticancer Agent ◽

Pancreatic Cancer Cell Line ◽

Cancer Cell Line ◽

Cycle Arrest ◽

M Phase ◽

P38 Pathway

Pancreatic cancer has a poor prognosis with a five-year survival rate of less than 10%. Moreover, chemotherapy is mostly rendered ineffective owing to chemotherapy resistance and cytotoxicity. Therefore, the development of effective therapeutic strategies and novel drugs against pancreatic cancer is an urgent need. Cucurbitacin D (CuD), a plant steroid derived from Trichosanthes kirilowii, is an anticancer agent effective against various cancer cell lines. However, the anticancer activity and molecular mechanism of CuD in pancreatic cancer remain unknown. Therefore, we aimed to investigate the anticancer activity and molecular mechanism of CuD in the human pancreatic cancer cell line, Capan-1. CuD induced cell cycle arrest at the G2/M phase, apoptosis, and reactive oxygen species generation in Capan-1 cell line. In addition, CuD induced the activation of the p38 MAPK signaling pathway that regulates apoptosis, which was also inhibited by N-acetyl-L-cysteine and the p38 inhibitor SB203580. These data suggest that CuD induces cell cycle arrest and apoptosis via the ROS/p38 pathway in Capan-1 pancreatic cancer cell line; hence, CuD is a promising candidate that should be explored further for its effectiveness as an anticancer agent against pancreatic cancer.

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