Extracellular vesicles-released parathyroid hormone-related protein from Lewis lung carcinoma induces lipolysis and adipose tissue browning in cancer cachexia

AbstractCancer cachexia is a metabolic disorder characterized by skeletal muscle wasting and white adipose tissue browning. Specific functions of several hormones, growth factors, and cytokines derived from tumors can trigger cachexia. Moreover, adipose tissue lipolysis might explain weight loss that occurs owing to cachexia. Extracellular vesicles (EVs) are involved in intercellular communication. However, whether EVs participate in lipolysis induced by cancer cachexia has not been thoroughly investigated. Using Lewis lung carcinoma (LLC) cell culture, we tested whether LLC cell-derived EVs can induce lipolysis in 3T3-L1 adipocytes. EVs derived from LLC cells were isolated and characterized biochemically and biophysically. Western blotting and glycerol assay were used to study lipolysis. LLC cell-derived EVs induced lipolysis in vivo and vitro. EVs fused directly with target 3T3-L1 adipocytes and transferred parathyroid hormone-related protein (PTHrP), activating the PKA signaling pathway in 3T3-L1 adipocytes. Blocking PTHrP activity in LLC-EVs using a neutralizing antibody and by knocking down PTHR expression prevented lipolysis in adipocytes. Inhibiting the PKA signaling pathway also prevents the lipolytic effects of EVs. In vivo, suppression of LLC-EVs release by knocking down Rab27A alleviated white adipose tissue browning and lipolysis. Our data showed that LLC cell-derived EVs induced adipocyte lipolysis via the extracellular PTHrP-mediated PKA pathway. Our data demonstrate that LLC-EVs induce lipolysis in vitro and vivo by delivering PTHrP, which interacts with PTHR. The lipolytic effect of LLC-EVs was abrogated by PTHR knockdown and treatment with a neutralizing anti-PTHrP antibody. Together, these data show that LLC-EV-induced lipolysis is mediated by extracellular PTHrP. These findings suggest a novel mechanism of lipid droplet loss and identify a potential therapeutic strategy for cancer cachexia.

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GHSR-1a is not Required for Ghrelin’s Anti-inflammatory and Fat-sparing Effects in Cancer Cachexia

10.1101/866376 ◽

2019 ◽

Author(s):

Haiming Liu ◽

Jiaohua Luo ◽

Bobby Guillory ◽

Ji-an Chen ◽

Pu Zang ◽

...

Keyword(s):

Adipose Tissue ◽

Energy Expenditure ◽

Lung Carcinoma ◽

Lewis Lung Carcinoma ◽

Cancer Cachexia ◽

Lewis Lung ◽

Anti Inflammatory

ABSTRACTAdipose tissue (AT) atrophy is a hallmark of cancer cachexia contributing to increased morbidity/mortality. Ghrelin has been proposed as a treatment for cancer cachexia partly by preventing AT atrophy. However, the mechanisms mediating ghrelin’s effects are incompletely understood, including the extent to which its only known receptor, GHSR-1a, is required for these effects. This study characterizes the pathways involved in AT atrophy in the Lewis Lung Carcinoma (LLC)-induced cachexia model and those mediating the effects of ghrelin in Ghsr+/+ and Ghsr−/− mice. We show that LLC causes AT atrophy by inducing anorexia, and increasing AT inflammation, thermogenesis and energy expenditure. These changes were greater in Ghsr−/−. Ghrelin administration prevented LLC-induced anorexia only in Ghsr+/+, but prevented WAT inflammation and atrophy in both genotypes, although its effects were greater in Ghsr+/+. LLC-induced increases in BAT inflammation, WAT and BAT thermogenesis, and energy expenditure were not affected by ghrelin. In conclusion, ghrelin ameliorates WAT inflammation, fat atrophy and anorexia in LLC-induced cachexia. GHSR-1a is required for ghrelin’s orexigenic effect but not for its anti-inflammatory or fat-sparing effects.

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Asian ginseng extract inhibits in vitro and in vivo growth of mouse lewis lung carcinoma via modulation of ERK-p53 and NF-κB signaling

Journal of Cellular Biochemistry ◽

10.1002/jcb.22778 ◽

2010 ◽

Vol 111 (4) ◽

pp. 899-910 ◽

Cited By ~ 38

Author(s):

Vincent Kam Wai Wong ◽

Simon Shiu Fai Cheung ◽

Ting Li ◽

Zhi-Hong Jiang ◽

Jing-Rong Wang ◽

...

Keyword(s):

Lung Carcinoma ◽

Lewis Lung Carcinoma ◽

Lewis Lung ◽

Ginseng Extract ◽

In Vivo Growth

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Relationship of cell cycle parameters to in vitro and in vivo chemosensitivity for a series of Lewis lung carcinoma lines

European Journal of Cancer ◽

10.1016/0959-8049(92)90537-c ◽

1992 ◽

Vol 28 (8-9) ◽

pp. 1427-1431 ◽

Cited By ~ 13

Author(s):

Karen M. Holdaway ◽

Graeme J. Finlay ◽

Bruce C. Baguley

Keyword(s):

Cell Cycle ◽

Lung Carcinoma ◽

Lewis Lung Carcinoma ◽

Lewis Lung ◽

Relationship Of

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Sex-Specific Survival Advantage with Parathyroid Hormone–Related Protein in Non–Small Cell Lung Carcinoma Patients

Clinical Cancer Research ◽

10.1158/1078-0432.ccr-05-0930 ◽

2006 ◽

Vol 12 (2) ◽

pp. 499-506 ◽

Cited By ~ 14

Author(s):

Randolph H. Hastings ◽

Ann M.P. Laux ◽

Andrea Casillas ◽

Ronghui Xu ◽

Zenaida Lukas ◽

...

Keyword(s):

Parathyroid Hormone ◽

Lung Carcinoma ◽

Small Cell Lung Carcinoma ◽

Small Cell ◽

Survival Advantage ◽

Related Protein ◽

Small Cell Lung ◽

Cell Lung Carcinoma ◽

Parathyroid Hormone Related Protein

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Effect of Micelle-Incorporated Cisplatin With Sizes Ranging From 8 to 40 nm for the Therapy of Lewis Lung Carcinoma

Frontiers in Pharmacology ◽

10.3389/fphar.2021.632877 ◽

2021 ◽

Vol 12 ◽

Author(s):

Zhicheng Wang ◽

Yumin Li ◽

Tong Zhang ◽

Hongxia Li ◽

Zhao Yang ◽

...

Keyword(s):

Block Copolymers ◽

Lung Carcinoma ◽

Lewis Lung Carcinoma ◽

Drug Loading ◽

Complexation Reaction ◽

Lewis Lung ◽

Antitumor Effects ◽

Lung Carcinoma Cells

Insufficient transport of therapeutic cargo into tumor bed is a bottleneck in cancer nanomedicine. Block copolymers are promising carriers with smaller particle size by ratio modification. Here, we constructed cisplatin nanoparticles with sizes ranging from 8 to 40 nm to study the permeability and therapy of Lewis lung carcinoma. We synthesized methoxypoly(ethylene glycol)2000-block poly(L-glutamic acid sodium salt)1979 loading cisplatin through complexation reaction. The cisplatin nanomedicine has high drug loading and encapsulation efficiency. In vitro data demonstrated that cisplatin nanoparticles had equivalent growth-inhibiting effects on Lewis lung carcinoma cells compared to free cisplatin. In vivo evidences showed cisplatin nanoparticles had superior antitumor effects on the Lewis lung carcinoma mouse model with no obvious side effects. All results indicated that optimizing the ratio of block copolymers to obtain smaller sized nanomedicine could act as a promising strategy for overcoming the inadequate accumulation in poorly vascularized tumors.

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