Serine protease HtrA1 modulates chemotherapy-induced cytotoxicity.
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.
Chien
Jeremy
J
Department of Laboratory Medicine and Experimental Pathology, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA, Medical Oncology Unit and Department of Histopathology, San Salvatore Hospital, Pesaro, Italy.
Aletti
Giovanni
G
Baldi
Alfonso
A
Catalano
Vincenzo
V
Muretto
Pietro
P
Keeney
Gary L
GL
Kalli
Kimberly R
KR
Staub
Julie
J
Ehrmann
Michael
M
Cliby
William A
WA
Lee
Yean Kit
YK
Bible
Keith C
KC
Hartmann
Lynn C
LC
Kaufmann
Scott H
SH
Shridhar
Viji
V
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000595:Amino Acid Sequence; D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use; D020169:Caspases / Q000378:metabolism; D016923:Cell Death; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000627:therapeutic use; D004358:Drug Therapy; D004789:Enzyme Activation; D005260:Female; D000074289:High-Temperature Requirement A Serine Peptidase 1; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D017239:Paclitaxel / Q000627:therapeutic use; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism*; D013274:Stomach Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology
D000972:Antineoplastic Agents, Phytogenic; D034741:RNA, Small Interfering; D000074289:High-Temperature Requirement A Serine Peptidase 1; C474012:HTRA1 protein, human; D012697:Serine Endopeptidases; D020169:Caspases; D017239:Paclitaxel; D002945:Cisplatin