Hyaluronan synthase HAS2 promotes chemoresistance by upregulating NRF2 expression

[Speaker] Bo-hyun Choi:1
[Co-author] In-Geun Ryoo:1, Mi-Kyoung Kwak:1
1:College of Pharmacy, The Catholic University of Korea, Korea

The glycosaminoglycan hyaluronic acid (HA) and its cell surface receptors CD44 have been implicated in cancer progression. The transcription factor NF-E2-related factor 2 (NRF2) has pivotal roles in the induction of cytoprotective genes in response to oxidative stress. In this study, we investigated the relevance of NRF2 and hyaluronan synthase HAS2 on chemoresistance using two different doxorubicin-resistant cancer cells (MCF7-DR and SNU620-DR). Firstly, NRF2 protein level is significantly upregulated in doxorubicin-resistant cancer cells compared to its parental cells. Protein levels of CD44 and HAS2 were highly expressed in MCF7-DR and SNU620-DR cells. Next, we explored the relationship between HAS2 level and NRF2 pathway. Firstly, we suppressed HAS2 mRNA level using siRNA. Inhibition of HAS2 expression leads to a significant decrease in NRF2 level. When cancer cells were incubated with HA (0-50 ug/ml), NRF2 level was gradually increased. Furthermore, treatment of pharmacological HAS2 inhibitor (4-methylumbelliferone; 4-MU) generates more reactive oxygen species and attenuates doxorubicin resistance in MCF7-DR and SNU620DR cells. Collectively, these results indicate that HAS2-mediated NRF2 activation make favorable environments for doxorubicin-resistant cancer cells. In addition, downregulation of HAS2 reduced NRF2 expression, which renders cancer cells susceptible to anticancer therapy.
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