Strigolactone analogues induce apoptosis through activation of p38 and the stress response pathway in cancer cell lines and in conditionally reprogrammed primary prostate cancer cells.
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Claire B Pollock1,2, Sara McDonough1, Victor S. Wang1, Hyojung Lee1, Lymor Ringer2,3,4, Xin Li5, Cristina Prandi6, Richard J. Lee7, Adam S. Feldman7, Hinanit Koltai8, Yoram Kapulnik9, Olga C Rodriguez2,3,4, Richard Schlegel2,3,4, Christopher Albanese2,3,4, and Ronit I. Yarden1,2
1 Department of Human Science, Georgetown University Medical Center, NW Washington DC
2 Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, NW Washington DC
3 Department of Pathology, Georgetown University Medical Center, NW Washington DC
4 Center for Cellular Reprogramming, Georgetown University Medical Center, NW Washington DC
5 Department of Biostatistics, Bioinformatics and Biomathematics Georgetown University Medical Center, NW Washington DC
6 Department of Chemistry, University Turin, Torino, Italy,
7 Massachusetts General Hospital, Boston, MA,
8 Department of Ornamental Horticulture, Agricultural Research Organization (ARO), Bet Dagan, Israel
9 Department of Field Crops and Natural Resources Institute of Plant Sciences, Agricultural Research Organization (ARO), Bet Dagan, Israel
Ronit I. Yarden, email:
Keywords: Plant hormone, cell cycle arrest, apoptosis, stress response, p38-MAPK
Received: February 14, 2014 Accepted: March 31, 2014 Published: April 2, 2014
Strigolactones are a novel class of plant hormones produced in roots and regulate shoot and root development. We have previously shown that synthetic strigolactone analogues potently inhibit growth of breast cancer cells and breast cancer stem cells. Here we show that strigolactone analogues inhibit the growth and survival of an array of cancer-derived cell lines representing solid and non-solid cancer cells including: prostate, colon, lung, melanoma, osteosarcoma and leukemic cell lines, while normal cells were minimally affected. Treatment of cancer cells with strigolactone analogues was hallmarked by activation of the stress-related MAPKs: p38 and JNK and induction of stress-related genes; cell cycle arrest and apoptosis evident by increased percentages of cells in the sub-G1 fraction and Annexin V staining. In addition, we tested the response of patient-matched conditionally reprogrammed primary prostate normal and cancer cells. The tumor cells exhibited significantly higher sensitivity to the two most potent SL analogues with increased apoptosis confirmed by PARP1 cleavage compared to their normal counterpart cells. Thus, Strigolactone analogues are promising candidates for anticancer therapy by their ability to specifically induce cell cycle arrest, cellular stress and apoptosis in tumor cells with minimal effects on growth and survival of normal cells.
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