Monoclonal antibody against CXCL1 (HL2401) as a novel agent in suppressing IL6 expression and tumoral growth

Makito Miyake, Hideki Furuya, Sayuri Onishi, Kanani Hokutan, Satoshi Anai, Owen Chan, Sixiang Shi, Kiyohide Fujimoto, Steve Goodison, Weibo Cai, Charles J. Rosser

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

Abstract

Rationale: The expression of the chemokine (C-X-C motif) ligand 1 (CXCL1), an inflammatory protein, has been reported to be up-regulated in many human cancers. The mechanisms through which aberrant cellular CXCL1 levels promote specific steps in tumor growth and progression are unknown. Methods: We described the anticancer effects and mechanism of action of HL2401, a monoclonal antibody directed at CXCL1 with in vitro and in vivo data on bladder and prostate cancers. Results: HL2401 inhibited proliferation and invasion of bladder and prostate cells along with disrupting endothelial sprouting in vitro. Furthermore, novel mechanistic investigations revealed that CXCL1 expression stimulated interleukin 6 (IL6) expression and repressed tissue inhibitor of metalloproteinase 4 (TIMP4). Systemic administration of HL2401 in mice bearing bladder and prostate xenograft tumors retarded tumor growth through the inhibition of cellular proliferation and angiogenesis along with an induction of apoptosis. Our findings reveal a previously undocumented relationship between CXCL1, IL6 and TIMP4 in solid tumor biology. Principal conclusions: Taken together, our results argue that CXCL1 plays an important role in sustaining the growth of bladder and prostate tumors via up-regulation of IL6 and down-regulation of TIMP4. Targeting these critical interactions with a CXCL1 monoclonal antibody offers a novel strategy to therapeutically manage bladder and prostate cancers.

Original languageEnglish (US)
Pages (from-to)853-867
Number of pages15
JournalTheranostics
Volume9
Issue number3
DOIs
StatePublished - 2019

Keywords

  • Bladder cancer
  • CXCL1
  • IL6
  • Prostate cancer
  • TIMP4

ASJC Scopus subject areas

  • Medicine (miscellaneous)
  • Pharmacology, Toxicology and Pharmaceutics (miscellaneous)

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