Abstract
Higher levels of hyaluronan (HA) and its receptors CD44 and RHAMM have been associated with poor prognosis and metastasis in NSCLC. In the current study, our goal was to define, using cellular and orthotopic lung tumor models, the role of HA-CD44/RHAMM signaling in lung carcinogenesis and to assess the potential of triptolide to block HA-CD44/RHAMM signaling and thereby suppress the development and progression of lung cancer. Triptolide reduced the viability of five non-small cell lung cancer (NSCLC) cells, the proliferation and self-renewal of pulmospheres, and levels of HA synthase 2 (HAS2), HAS3, HA, CD44, RHAMM, EGFR, Akt and ERK, but increased the cleavage of caspase 3 and PARP. Silencing of HAS2, CD44 or RHAMM induced similar effects. Addition of excess HA to the culture media completely abrogated the effects of triptolide and siRNAs targeting HAS2, CD44, or RHAMM. In an orthotopic lung cancer model in nude rats, intranasal administration of liposomal triptolide (400 μg/kg) for 8 weeks significantly reduced lung tumor growth as determined by bioluminescence imaging, lung weight measurements and gross and histopathological analysis of tumor burden. Also, triptolide suppressed expressions of Ki-67, a marker for cell proliferation, HAS2, HAS3, HA, CD44, and RHAMM in lung tumors. Overall, our results provide a strong rationale for mitigating lung cancer by targeting the HA-CD44/RHAMM signaling axis.
Highlights
Hyaluronan (HA), a linear polysaccharide comprised of D-glucuronic acid and N-acetyl-Dglucosamine, is synthesized by three membrane-bound HA synthases, HAS1, HA synthase 2 (HAS2), and Hyaluronan Acid Synthase 3 (HAS3) [1]
We examined the efficacy of triptolide to inhibit the growth of non-small cell lung cancer (NSCLC) cells in vitro and in vivo and if targeting of HA-CD44/Receptor for Hyaluronic Acid-Mediated Motility (RHAMM) contributes to the growth inhibitory effects of the drug
We found that the HA-CD44/RHAMM signaling pathway plays a crucial role in the proliferation and survival of NSCLC cells and that low concentrations of triptolide significantly reduced the growth of these cells by targeting the HA-CD44/RHAMM signaling axis
Summary
Hyaluronan (HA), a linear polysaccharide comprised of D-glucuronic acid and N-acetyl-Dglucosamine, is synthesized by three membrane-bound HA synthases, HAS1, HAS2, and HAS3 [1]. Though HA signals through interaction with several cell surface receptors, the best characterized receptors in cancer cells are CD44 and RHAMM (receptor for hyaluronic acid-mediated motility). CD44, a transmembrane glycoprotein, is expressed as a wide variety of isoforms in many cells, and implicated in increased cancer cell migration, invasion, and metastasis [6,7,8,9]. It attracted considerable interest as a cancer stem cell (CSC) marker in several malignancies of hematopoietic and epithelial origin [9]. Targeting HA-CD44/RHAMM signaling axis could be a promising strategy for the prevention and treatment of lung cancer
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