NDLI: Serine protease HtrA1 modulates chemotherapy-induced cytotoxicity

Content Provider	PubMed Central
Author	Chien, Jeremy Aletti, Giovanni Baldi, Alfonso Catalano, Vincenzo Pietro, Muretto Keeney, Gary L. Kalli, Kimberly R. Staub, Julie Ehrmann, Michael Cliby, William A. Lee, Yean Kit Bible, Keith C. Hartmann, Lynn C. Kaufmann, Scott H. Shridhar, Viji
Copyright Year	2006
Abstract	Resistance to chemotherapy presents a serious challenge in the successful treatment of various cancers and is mainly responsible for mortality associated with disseminated cancers. Here we show that expression of HtrA1, which is frequently downregulated in ovarian cancer, influences tumor response to chemotherapy by modulating chemotherapy-induced cytotoxicity. Downregulation of HtrA1 attenuated cisplatin- and paclitaxel-induced cytotoxicity, while forced expression of HtrA1 enhanced cisplatin- and paclitaxel-induced cytotoxicity. HtrA1 expression was upregulated by both cisplatin and paclitaxel treatment. This upregulation resulted in limited autoproteolysis and activation of HtrA1. Active HtrA1 induces cell death in a serine protease–dependent manner. The potential role of HtrA1 as a predictive factor of clinical response to chemotherapy was assessed in both ovarian and gastric cancer patients receiving cisplatin-based regimens. Patients with ovarian or gastric tumors expressing higher levels of HtrA1 showed a higher response rate compared with those with lower levels of HtrA1 expression. These findings uncover what we believe to be a novel pathway by which serine protease HtrA1 mediates paclitaxel- and cisplatin-induced cytotoxicity and suggest that loss of HtrA1 in ovarian and gastric cancers may contribute to in vivo chemoresistance.
Related Links	http://dx.doi.org/10.1172/jci27698
Ending Page	2004
Page Count	11
Starting Page	1994
File Format	PDF
ISSN	00219738
Journal	Journal of Clinical Investigation
Issue Number	7
Volume Number	116
Language	English
Publisher	American Society for Clinical Investigation
Publisher Date	2006-07-03
Access Restriction	Open
Rights Holder	American Society for Clinical Investigation
Subject Keyword	Medicine(all) Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Medicine

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4	Project PI / Joint PI	Principal Investigator and Joint Principal Investigators of the project	Dr. B. Sutradhar bsutra@ndl.gov.in Prof. Saswat Chakrabarti will be added soon
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