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Title: EFFECT OF THE PLANT PEPTIDE REGULATOR, PHYTOSULFOKINE-ALPHA, ON THE GROWTH AND TAXOL PRODUCTION FROM TAXUS SP. SUSPENSION CULTURES

Author
item KIM, BEUM JUN - CORNELL UNIVERSITY
item Gibson, Donna
item SHULER, MICHAEL - CORNELL UNIVERSITY

Submitted to: Biotechnology and Bioengineering
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 6/15/2006
Publication Date: 7/5/2006
Citation: Kim, B., Gibson, D.M., Shuler, M.L. 2006. Effect of the plant peptide regulator, phytosulfokine-alpha, on the growth and taxol production from taxus sp. suspension cultures. Biotechnology and Bioengineering. 95:8-14.

Interpretive Summary: Paclitaxel (Taxol™) is a potent chemotherapeutic drug with proven utility against a range of cancers, including lung, breast, and ovarian cancer. The limited supply of this drug from the original tree source prompted the development of alternative sources of production, including the use of plant cell cultures. Taxol derived from plant cell cultures has been commercialized, but work is still needed to optimize production and understand the underlying mechanisms regulating production. One common problem in plant cell cultures is the loss of productivity when cultures are maintained in long term (e.g. several years) culture. No general method to rescue such cultures and return them to high productivity exists. In this work, the peptide plant regulator, PSK-', was tested in Taxus cultures to determine its effect on secondary metabolism as represented by Taxol™ (paclitaxel) production. Optimal concentration and addition time of PSK-', alone and in combination with the known elicitor, methyl jasmonate (MeJA),for the production of Taxol were determined. This report is the first to examine possible synergistic effects of a protein regulator (PSK-') with an elicitor (MeJA) of secondary metabolism and to rescue productivity of cell lines that were no longer producing Taxol.

Technical Abstract: Phytosulfokine-' (PSK-') is a small plant peptide (5 amino acids) that displays characteristics typically associated with animal peptide hormones. It was originally isolated based on its mitogenic activity with plant cultures. PSK-' has been reported to increase production of tropane alkaloids from Atropa belladonna, but its general influence on secondary metabolite production is unknown. The studies reported in this paper were initiated to better understand the effects of PSK-' supplementation on production of Taxol™ (paclitaxel) from plant cell cultures of Taxus sp. particularly when methyl jasmonate is added as an elicitor of secondary metabolism. The response to PSK-' supplementation was cell line dependent. Taxus cuspidata P93AF showed no statistically significant response to PSK-' supplementation while Taxus canadensis C93AD and T. cuspidata PO93X displayed a concentration-dependent response (up to 100 nM PSK-' added in first 24 hours) with a decrease in initial growth rate, an increase in cell density (dry weight/fresh weight), and increased Taxol production. More remarkably with Taxus canadensis (C93AD), a very strong synergistic response of PSK-' (100 nM) and methyl jasmonate (MeJA, 100 'M) elicitation was observed, resulting in Taxol level of 35.3±2.1 mg/L or 1.83±0.02 mg Taxol/g dry cell weight achieved at day 21, a level of approximately ten fold higher than for either treatment by itself. While this absolute level of production is not exceptional, it demonstrates that cultures which have lost productivity due to extended culture periods (e.g. 10 years) can be partially rescued with this synergistic treatment.