(PO06-09-22) Paracrine Signaling From Pancreatic Ductal Cancer Cells Induced Programmed-Cell Death in 3T3-L1 Adipocytes Through Apoptosis and Ferroptosis

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Presenting Author(s)

Vivien Khoo, MS, RDN
– Doctoral Student, University of Massachusetts Amherst, Shutesbury, Massachusetts, United States

Co-Author(s)

YK

Young-Cheul Kim, Ph.D.
– Associate Professor, University of Massachusetts Amherst, School of Public Health & Health Sciences, Department of Nutrition, Amherst, Massachusetts, United States
MH

Micheal Hollingsworth
– University of Nebraska Medical Center
SK

So-youn Kim
– University of Nebraska Medical Center
SC

Soonkyu Chung, Ph.D.
– Associate Professor, University of Massachusetts Amherst, School of Public Health & Health Sciences, Department of Nutrition, Amherst, Massachusetts, United States

Disclosure(s):

Vivien Khoo, MS, RDN: No relevant financial relationship(s) with ineligible companies to disclose.

Objectives: Cancer cachexia is a prominent feature of patients with pancreatic ductal adenocarcinoma (PDAC). Cachexia is characterized by aberrant inflammatory responses, rapid loss of fat and muscle mass. Emerging evidence revealed that adipose tissue loss precedes muscle loss in those with cancer cachexia, suggesting that blocking cachectic fat loss is a therapeutic target. However, the underlying mechanisms by which cancer cells promote fat loss have not yet been established. We aim to investigate the molecular mechanisms behind the cachectic fat loss in PDAC patients.

Methods: The cell line derived from PDAC KPC mice (Kras^G12D;Trp53^R172H;Pdx1-Cre) was cultured, and conditioned-medium (CM) was collected for detecting proinflammatory cytokine levels by ELISA. An in vitro model was used to determine paracrine crosstalk between PADC and adipose tissue by transferring conditioned-medium of KPC (KPC-CM) to fully differentiated 3T3-L1 adipocytes. The effects of KPC-CM on lipolysis, lipogenesis- and iron homeostasis-related protein, proinflammatory gene expression, and signaling pathways for programmed cell death were examined. Intracellular free iron concentration and ROS production were also determined by using fluorometric assays.

Results: Our findings showed that CM of KPC cells contains various proinflammatory cytokines and chemokines associated with immune cell infiltration and oxidative stress, including CXCL1, LIX, CCL11, CCL2, IL-12, and TNFa. Addition of KPC-CM to 3T3-L1 adipocytes promoted glycerol release and phosphorylation of hormone-sensitive lipase in a dose-dependent manner, supporting augmented lipolysis. Moreover, KPC-CM reduced the adipocyte-specific gene and protein expression and promoted caspase 3-mediated apoptotic cell death. Concurrently, KPC-CM induced modification of iron metabolism, including the decreased expression of glutathione peroxidase 4 (GPX4) and increased nuclear receptor coactivator 3 (NCOA4), two biomarkers for iron-dependent programmed cell death, ferroptosis. In parallel, KPC-CM increased the intracellular Fe²⁺ levels and ROS production in 3T3-L1 adipocytes.

Conclusions: Collectively, our results revealed that the crosstalk between adipocyte tissue and PDAC CM triggers deregulation of iron homeostasis and lipid metabolism, leading to programmed cell death of adipocytes.

Funding Sources: N/A