Hepatocellular carcinoma show the highest relative-risk increase as a consequence of obesity compared to some other common forms of cancer. Recent studies have established that obesity is an endocrine disorder and its endocrine effects are mediated by the adipocytokines. Adiponectin, an adipocytokine proposed to have therapeutic potential, is inversely associated with obesity. Importantly, lower levels of serum adiponectin are associated with high risk of cancers such as endometrial, breast, gastric, colorectal cancer. My preliminary studies show that adiponectin inhibits proliferation, induces apoptosis and activates AMPK in hepatocellular carcinoma cells. Hypothesis: An integral part of the progression of hepatocellular carcinoma is the acquisition of the invasive and metastatic properties. This proposal will examine the hypothesis that adiponectin suppresses the growth and metastatic potential of hepatocellular carcinoma cells by increased crosstalk between AMPK and LKB1-TSC2-mTOR pathway. Objectives: (1) To demonstrate that adiponectin inhibits metastatic properties of hepatocellular carcinoma. 2) To elucidate the potential signal-transduction mechanisms involved in adiponectin action. 3) To examine whether adiponectin inhibits hepatocellular carcinoma tumorigenesis in nude mice. Study design: The inhibition of metastatic potential of hepatocellular carcinoma cell line HepG2 by adiponectin will be analyzed using various growth, invasion, migration and anoikis assays. The signal transduction pathway involved in the biological function of adiponectin involves AMPK activation. Both upstream and downstream components of this pathway will be elucidated using kinase assays, western blotting, RT-PCR analysis. Selective inhibition using siRNA silencing will be used to define the function of adiponectin receptors. Tumor Xenograft [sic] model using athymic nude mice with HepG2 cells will be utilized to show the protective role of adiponectin in vivo. Relevance to public: Obesity, a major health problem in US is a significant risk factor for hepatocellular carcinoma and its endocrine effects are mediated by adipocytokines. The studies proposed here are designed to establish adiponectin as a novel negative regulator of hepatocellular carcinoma and systemically delineate the signaling mechanisms involved in its action. Delineation of the protective role of adiponectin in hepatocellular carcinoma thus presents new preventive and therapeutic options for patients.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Scientist Development Award - Research & Training (K01)
Project #
Application #
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Program Officer
Podskalny, Judith M,
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Emory University
Internal Medicine/Medicine
Schools of Medicine
United States
Zip Code
Avtanski, Dimiter B; Nagalingam, Arumugam; Tomaszewski, Joseph E et al. (2016) Indolo-pyrido-isoquinolin based alkaloid inhibits growth, invasion and migration of breast cancer cells via activation of p53-miR34a axis. Mol Oncol 10:1118-32
Block, Keith I; Gyllenhaal, Charlotte; Lowe, Leroy et al. (2015) Designing a broad-spectrum integrative approach for cancer prevention and treatment. Semin Cancer Biol 35 Suppl:S276-S304
Feitelson, Mark A; Arzumanyan, Alla; Kulathinal, Rob J et al. (2015) Sustained proliferation in cancer: Mechanisms and novel therapeutic targets. Semin Cancer Biol 35 Suppl:S25-S54
Avtanski, Dimiter B; Nagalingam, Arumugam; Kuppusamy, Panjamurthy et al. (2015) Honokiol abrogates leptin-induced tumor progression by inhibiting Wnt1-MTA1-?-catenin signaling axis in a microRNA-34a dependent manner. Oncotarget 6:16396-410
Saxena, Neeraj K; Anania, Frank A (2015) Adipocytokines and hepatic fibrosis. Trends Endocrinol Metab 26:153-61
Nagalingam, Arumugam; Kuppusamy, Panjamurthy; Singh, Shivendra V et al. (2014) Mechanistic elucidation of the antitumor properties of withaferin a in breast cancer. Cancer Res 74:2617-29
Avtanski, Dimiter B; Nagalingam, Arumugam; Bonner, Michael Y et al. (2014) Honokiol inhibits epithelial-mesenchymal transition in breast cancer cells by targeting signal transducer and activator of transcription 3/Zeb1/E-cadherin axis. Mol Oncol 8:565-80
Saxena, Neeraj K; Sharma, Dipali (2013) Multifaceted leptin network: the molecular connection between obesity and breast cancer. J Mammary Gland Biol Neoplasia 18:309-20
Khurana, Sandeep; Jadeja, Ravirajsinh; Twaddell, William et al. (2013) Effects of modulating M3 muscarinic receptor activity on azoxymethane-induced liver injury in mice. Biochem Pharmacol 86:329-38
Knight, Brandi B; Oprea-Ilies, Gabriela M; Nagalingam, Arumugam et al. (2011) Survivin upregulation, dependent on leptin-EGFR-Notch1 axis, is essential for leptin-induced migration of breast carcinoma cells. Endocr Relat Cancer 18:413-28

Showing the most recent 10 out of 20 publications