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COMPARISON STUDY OF THE EFFECTS OF ZERUMBONE AND AG490 IN HUMAN RENAL CELL CARCINOMA ON THE ACTIVATION OF THE JANUS KINASE PATHWAY AND CELL SURVIVAL
Author(s) -
Walker Zachary,
Duncan Anthony,
Bellomo Tiffany,
Budd Kaitlin,
Polina Aws,
Hafron Jason,
BanesBerceli Amy
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.671.4
Subject(s) - sunitinib , janus kinase , cancer research , medicine , renal cell carcinoma , viability assay , janus kinase 2 , jak stat signaling pathway , cell culture , cell growth , cell , chemistry , biology , tyrosine kinase , cytokine , receptor , genetics , biochemistry
In the United States, Renal Cell Carcinoma (RCC) accounts for 9 out of 10 cases of kidney cancer. Approximately 33% of the patients present with metastatic disease and of those initially treated by surgical resection 40–50% will develop recurrent metastatic disease.13,860 people are estimated to die from RCC in 2016 due to poor responsiveness to the current chemotherapy medications. Development of new therapies is limited because the molecular mechanisms of RCC and the chemoresistance are poorly understood. However, we and others have shown that alterations in the levels of the Janus Kinase (JAK2) and Signal transducers of activators of transcription (STAT) pathway may be involved as it has been implicated in invasiveness and cell survival in RCC cell lines. We hypothesize that altered activation of the JAK/STAT/SHP‐1 pathway contributes to the development of RCC and the chemoresistance observed. To test this hypothesis we used the RCC cell line (ATCC) and we treated the cells for 24 hours with the JAK2 inhibitor AG490 and sunitinib (standard chemotherapy agent) alone and in combination. After 24 hrs we found a 20% decrease in cell viability in the AG490 treated cells but not in the sunitinib treated cells. Combination of AG490 and sunitinib for 24 hrs resulted in a 40% decrease in cell viability. We also treated cells for 24, and 48 hrs with AG490 to directly inhibit JAK2 and with zerumbone, an inducer of SHP‐1 activity, which will indirectly decrease JAK2 phosphorylation and activation. At 24 hrs we found significant decreases in JAK2 phosphorylation levels with both and almost undetectable levels by 48 hrs. The STAT1 and STAT3 levels were only decreased significantly after 48 hrs of treatment with both zerumbone and AG490. We also treated cells with these inhibitors and measured cell viability for 24, 48, 72 and 96 hrs. We found an 80% reduction in cell viability at 96 hrs of treatment with both the zerumbone and AG490. There data suggest that inhibition of JAK2 is a viable clinical target for future therapy as it enhanced the response to sunitinib as well as decreased cell viability on its own. Support or Funding Information Oakland University Center for Biomedical Research