Oncotarget

Research Papers:

Triptolide suppresses the in vitro and in vivo growth of lung cancer cells by targeting hyaluronan-CD44/RHAMM signaling

Jung Min Song, Kalkidan Molla, Arunkumar Anandharaj, Ingrid Cornax, M. Gerard O`Sullivan, Ameya R. Kirtane, Jayanth Panyam and Fekadu Kassie _

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Oncotarget. 2017; 8:26927-26940. https://doi.org/10.18632/oncotarget.15879

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Abstract

Jung Min Song1, Kalkidan Molla1, Arunkumar Anandharaj1, Ingrid Cornax1, M. Gerard O`Sullivan1,2, Ameya R. Kirtane3, Jayanth Panyam3, Fekadu Kassie1,4

1Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA

2Department of Veterinary Population Medicine, College of Veterinary Medicine, University of Minnesota, Saint Paul, MN 55108, USA

3Department of Pharmaceutics, University of Minnesota, Minneapolis, MN 55455, USA

4Department of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Minnesota, Saint Paul, MN 55108, USA

Correspondence to:

Fekadu Kassie, email: kassi012@umn.edu

Keywords: triptolide, hyaluronan, hyaluronan receptor, NSCLC, orthotopic

Received: November 30, 2016     Accepted: February 15, 2017     Published: March 03, 2017

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.


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