Serine protease HtrA1 modulates chemotherapy-induced cytotoxicity

Jeremy Chien, Giovanni Aletti, Alfonso Baldi, Vincenzo Catalano, Pietro Muretto, Gary Keeney, Kimberly R. Kalli, Julie Staub, Michael Ehrmann, William Arthur Cliby, Yean Kit Lee, Keith C. Bible, Lynn C. Hartmann, Scott H Kaufmann, Vijayalakshmi Shridhar

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)1994-2004
Number of pages11
JournalJournal of Clinical Investigation
Volume116
Issue number7
DOIs
StatePublished - Jul 3 2006

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Serine Proteases
Ovarian Neoplasms
Drug Therapy
Stomach Neoplasms
Neoplasms
Down-Regulation
Cisplatin
Stomach
Cell Death
Up-Regulation
Mortality
TP protocol
Therapeutics

ASJC Scopus subject areas

  • Medicine(all)

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Serine protease HtrA1 modulates chemotherapy-induced cytotoxicity. / Chien, Jeremy; Aletti, Giovanni; Baldi, Alfonso; Catalano, Vincenzo; Muretto, Pietro; Keeney, Gary; Kalli, Kimberly R.; Staub, Julie; Ehrmann, Michael; Cliby, William Arthur; Lee, Yean Kit; Bible, Keith C.; Hartmann, Lynn C.; Kaufmann, Scott H; Shridhar, Vijayalakshmi.

In: Journal of Clinical Investigation, Vol. 116, No. 7, 03.07.2006, p. 1994-2004.

Research output: Contribution to journalArticle

Chien, J, Aletti, G, Baldi, A, Catalano, V, Muretto, P, Keeney, G, Kalli, KR, Staub, J, Ehrmann, M, Cliby, WA, Lee, YK, Bible, KC, Hartmann, LC, Kaufmann, SH & Shridhar, V 2006, 'Serine protease HtrA1 modulates chemotherapy-induced cytotoxicity', Journal of Clinical Investigation, vol. 116, no. 7, pp. 1994-2004. https://doi.org/10.1172/JCI27698
Chien, Jeremy ; Aletti, Giovanni ; Baldi, Alfonso ; Catalano, Vincenzo ; Muretto, Pietro ; Keeney, Gary ; Kalli, Kimberly R. ; Staub, Julie ; Ehrmann, Michael ; Cliby, William Arthur ; Lee, Yean Kit ; Bible, Keith C. ; Hartmann, Lynn C. ; Kaufmann, Scott H ; Shridhar, Vijayalakshmi. / Serine protease HtrA1 modulates chemotherapy-induced cytotoxicity. In: Journal of Clinical Investigation. 2006 ; Vol. 116, No. 7. pp. 1994-2004.
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