Targeting hyaluronic acid synthase-3 (HAS3) for the treatment of advanced renal cell carcinoma

Jiaojiao Wang, Andre R. Jordan, Huabin Zhu, Sarrah L. Hasanali, Eric Thomas, Soum D. Lokeshwar, Daley S. Morera, Sung Alexander, Joseph McDaniels, Anuj Sharma, Karina Aguilar, Semih Sarcan, Tianyi Zhu, Mark S. Soloway, Martha K. Terris, Muthusamy Thangaraju, Luis E. Lopez, Vinata B. Lokeshwar

Research output: Contribution to journalArticlepeer-review

Abstract

Background: Hyaluronic acid (HA) promotes cancer metastasis; however, the currently approved treatments do not target HA. Metastatic renal carcinoma (mRCC) is an incurable disease. Sorafenib (SF) is a modestly effective antiangiogenic drug for mRCC. Although only endothelial cells express known SF targets, SF is cytotoxic to RCC cells at concentrations higher than the pharmacological-dose (5-µM). Using patient cohorts, mRCC models, and SF combination with 4-methylumbelliferone (MU), we discovered an SF target in RCC cells and targeted it for treatment. Methods: We analyzed HA-synthase (HAS1, HAS2, HAS3) expression in RCC cells and clinical (n = 129), TCGA-KIRC (n = 542), and TCGA-KIRP (n = 291) cohorts. We evaluated the efficacy of SF and SF plus MU combination in RCC cells, HAS3-transfectants, endothelial-RCC co-cultures, and xenografts. Results: RCC cells showed increased HAS3 expression. In the clinical and TCGA-KIRC/TCGA-KIRP cohorts, higher HAS3 levels predicted metastasis and shorter survival. At > 10-µM dose, SF inhibited HAS3/HA-synthesis and RCC cell growth. However, at ≤ 5-µM dose SF in combination with MU inhibited HAS3/HA synthesis, growth of RCC cells and endothelial-RCC co-cultures, and induced apoptosis. The combination inhibited motility/invasion and an HA-signaling-related invasive-signature. We previously showed that MU inhibits SF inactivation in RCC cells. While HAS3-knockdown transfectants were sensitive to SF, ectopic-HAS3-expression induced resistance to the combination. In RCC models, the combination inhibited tumor growth and metastasis with little toxicity; however, ectopic-HAS3-expressing tumors were resistant. Conclusion: HAS3 is the first known target of SF in RCC cells. In combination with MU (human equivalent-dose, 0.6–1.1-g/day), SF targets HAS3 and effectively abrogates mRCC.

Original languageEnglish (US)
Article number421
JournalCancer Cell International
Volume22
Issue number1
DOIs
StatePublished - Dec 2022

Keywords

  • 4-methylumbelliferone
  • HAS3
  • Hyaluronic acid
  • Molecular targeting
  • Renal cell carcinoma
  • Sorafenib

ASJC Scopus subject areas

  • Oncology
  • Genetics
  • Cancer Research

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