Indiana University-Purdue University Indianapolis (IUPUI) / Cachexia, the involuntary loss of fat and muscle is associated with
pancreatic ductal adenocarcinoma (PDAC), contributing to its 90% 5-year
mortality rate. Elevated Interleukin-6 (IL-6) expression is associated with
cachexia severity and reduced survival in patients. IL-6 in cancer is well
documented, but IL-6 signaling crosstalk among tissues is not. IL-6 signals by
binding membrane-bound IL-6 receptor (IL-6R) (classical signaling) or soluble IL-
6R (sIL6R; trans-signaling) produced by shedding of the membrane receptor
primarily from muscle, liver and leukocytes. Herein I investigate the role of tumorderived
IL-6 on muscle and fat crosstalk in PDAC. Loss of IL-6 expression in
murine KPC PDAC cells was accomplished by CRISPR/Cas9 mutagenesis of the
Il6 gene. Orthotopic KPC IL-6 knockout (KPC-IL-6KO) tumor-bearing mice had
reduced cachexia, with attenuated fat loss and no significant muscle loss, and
longer survival versus KPC controls. Only KPC tumor-bearing mice had
significant myosteatosis, aberrant branched chain amino acid and fatty acid
metabolism, and reduced pyruvate entry into the TCA-cycle, determined by
increased pyruvate dehydrogenase kinase 4 (PDK4) expression in muscle.
Muscle was a main source of sIL6R, and fat a primary contributor of IL-6 in KPC
tumor-bearing mice. Myosteatosis leads to activation of lipid-sensitive kinases
like protein kinase C theta (PKCθ, gene name Prkcq) in muscle. KPC tumorbearing
mice had increased muscle PKCθ activation, and PKCθ is known to
regulate metabolism and inflammation. Prkcq-/- KPC tumor-bearing mice had
reduced cachexia and maintained muscle mass and force production versus wild
type tumor-bearing mice. Together these data implicate progressive signaling
mechanisms whereby tumor-derived IL-6 is associated with increased muscle
IL6R expression and fat lipolysis, promoting myosteatosis and muscle PKCθ
activation, ultimately increasing cachexia severity in PDAC. / 2021-11-03
| Identifer | oai:union.ndltd.org:IUPUI/oai:scholarworks.iupui.edu:1805/24616 |
| Date | 10 1900 |
| Creators | Rupert, Joseph Emil |
| Contributors | Zimmers, Teresa A., Broxmeyer, Hal E., Goebl, Mark G., O'Connell, Thomas M., Quilliam, Lawrence A. |
| Source Sets | Indiana University-Purdue University Indianapolis |
| Language | en_US |
| Detected Language | English |
| Type | Dissertation |
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