Honors Capstone Project
Date of Submission
William G. Kerr, Principal Investigator
John Belote, Professor & Faculty Advisor
Arts and Science
Capstone Prize Winner
Won Capstone Funding
Sciences and Engineering
Biology | Cancer Biology | Cell and Developmental Biology | Life Sciences
Aberrant hyperactivation of the phosphatidylinositol 3-kinase (PI3K) cell-signaling pathway, one of the most prominent cell growth, proliferation and survival pathways in the human body, has been observed in many forms of cancer. Upon deregulation, this pathway can facilitate the evasion of programmed cell death, the stimulation of autonomous growth, and the evasion of regular growth-inhibitory signals. While it was initially believed that the dephosphorylation activity of lipid phosphatases served to counteract the pathway by hydrolyzing phosphatidylinositol(3,4,5)trisphosphate (PtdIns(3,4,5)P3) to phosphatidylinositol(4,5)bisphosphate (PtdIns(4,5)P2), emerging evidence suggests that SH2-domain containing inositol 5’ phosphatase 1 and 2 (SHIP1/2) may in fact facilitate, rather than suppress, oncogenesis in certain contexts. We hypothesize, therefore, that chemical inhibition of SHIP would decrease phosphatidylinositol bisphosphate levels, thus reducing downstream activation of cell survival and proliferation effectors. Previous work in the Kerr lab identified a SHIP1 selective inhibitor (3AC) that was capable of killing malignant hematological cells but was ineffective against other, non-hematological malignancies. Therefore, this study sought to identify further, more effective inhibitors, particularly those capable of targeting both SHIP1 and SHIP2, as well as to investigate the overall effect such pan-SHIP inhibition has on blood and breast cancers. In this study, we identify several lead pan-SHIP inhibitors capable of preventing the hydrolysis of PtdIns(3,4,5)P3 to PtsIns(3,4)P2. Furthermore, we demonstrate the ability of these pan-SHIP inhibitors to reduce cell viability and to effectively kill leukemia, multiple myeloma, and breast cancer cells. In conclusion, this study suggests that the inhibition of SHIP1 and SHIP2 may hold great clinical promise as a novel therapeutic approach in the treatment of many different cancers.
Balch, Amamda, "A Novel Therapeutic Approach in Breast and Hematopoietic Cancers: Inhibition of SH2-Domain Containing Inositol 5' Phosphatase (SHIP)" (2013). Honors Capstone Projects - All. 56.
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