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Development of inhibitors for activated Cdc42‐associated kinase (ACK) to reverse v‐Ras‐induced cancerous phenotype of mammalian cells
Author(s) -
Shepherd Jaleel,
NurEKamal Alam,
Ahmed Ijaz
Publication year - 2018
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.2018.32.1_supplement.836.6
Subject(s) - cdc42 , apoptosis , microbiology and biotechnology , 3t3 cells , cell growth , biology , phenotype , cancer research , gtpase , rac1 , kinase , cell culture , chemistry , signal transduction , transfection , gene , biochemistry , genetics
The superfamily of Ras GTPase has been reported to control different aspects of mammalian cell growth. Our lab demonstrated a possible role of Ras‐Cdc42‐ACK signaling in the survival of v‐Ras‐transformed cells. We also found that ACK‐deficient v‐Ras transformed NIH 3T3 cells undergo apoptosis while the parental NIH 3T3 cells grow normally. We proposed a hypothesis that “ACK‐induced phosphorylation plays a critical role in the survival of Ras‐induced transformed cells”. Based on three‐dimensional structure of ACK, our lab in collaboration with other group screens chemicals to identify potential specific inhibitors for ACK. In this report, I will present computer aided screening protocol and the effect of these inhibitors on growth of v‐Ras‐induced transformed and parental NIH 3T3 cells. I have used software to screen and identify potential inhibitors for ACK. These inhibitors were then used to treat v‐Ras transformed and parental NIH 3T3 cells. The cell growth was monitored by MTT assay. I have further studied the effect of these inhibitors on gene expression using immunostaining, immunoblotting, and polymerase chain reaction. I have identified some compounds that have strong affinity for ACK and inhibit growth of v‐Ras transformed cells. Treatment of v‐Ras cells with these inhibitors was found to activate apoptosis. I have used several markers of apoptosis. These results will be described in this report. We are designing novel compounds with more specific binding to ACK. Development of specific ACK inhibitors will be useful in better understanding the role of ACK in the growth of normal and cancer cells. Support or Funding Information NIH‐RISE This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .