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Theranostics 2019; 9(3):853-867. doi:10.7150/thno.29553 This issue Cite

Research Paper

Monoclonal Antibody against CXCL1 (HL2401) as a Novel Agent in Suppressing IL6 Expression and Tumoral Growth

Makito Miyake^1*, Hideki Furuya^{2,3 *}, Sayuri Onishi¹, Kanani Hokutan^2,3, Satoshi Anai¹, Owen Chan², Sixiang Shi⁴, Kiyohide Fujimoto¹, Steve Goodison⁵, Weibo Cai^4✉, Charles J. Rosser^2,3,5✉

1. Nara Medical University, Department of Urology, Nara, Japan,
2. University of Hawaii Cancer Center, Clinical and Translational Research, Honolulu, Hawaii,
3. Department of Molecular Biosciences and Bioengineering, University of Hawaii at Manoa, Honolulu, HI USA
4. Department of Radiology, University of Wisconsin - Madison, Madison, Wisconsin, USA
5. Nonagen Bioscience Corporation, Jacksonville, Florida
*co-first authors

✉ Corresponding authors: Charles J. Rosser, MD, MBA, FACS, Professor, Cedars-Sinai Medical Center, Samuel Oschin Comprehensive Cancer Center. Tel 310-423-7600; Email deacdoccom and Weibo Cai, PhD, Departments of Radiology and Medical Physics, University of Wisconsin - Madison, Madison, WI 53705. Tel: 608-262-1749; Fax: 608-265-0614; Email: wcaiorg More

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.

Keywords: bladder cancer, CXCL1, IL6, prostate cancer, TIMP4

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