In vivo targeting of ADAM9 gene expression using lentivirus-delivered shRNA suppresses prostate cancer growth by regulating REG4 dependent cell cycle progression.
Cancer cells respond to stress by activating a variety of survival signaling pathways. A disintegrin and metalloproteinase (ADAM) 9 is upregulated during cancer progression and hormone therapy, functioning in part through an increase in reactive oxygen species. Here, we present in vitro and in vivo evidence that therapeutic targeting of ADAM9 gene expression by lentivirus-delivered small hairpin RNA (shRNA) significantly inhibited proliferation of human prostate cancer cell lines and blocked tumor growth in a murine model of prostate cancer bone metastasis. Cell cycle studies confirmed an increase in the G1-phase and decrease in the S-phase population of cancer cells under starvation stress conditions, which correlated with elevated intracellular superoxide levels. Microarray data showed significantly decreased levels of regenerating islet-derived family member 4 (REG4) expression in prostate cancer cells with knockdown of ADAM9 gene expression. This REG4 downregulation also resulted in induction of expression of p21(Cip1/WAF1), which negatively regulates cyclin D1 and blocks the G1/S transition. Our data reveal a novel molecular mechanism of ADAM9 in the regulation of prostate cancer cell proliferation, and suggests a combined modality of ADAM9 shRNA gene therapy and cytotoxic agents for hormone refractory and bone metastatic prostate cancer.
Ph.D. Program for Cancer Biology and Drug Discovery, China Medical University and Academia Sinica, Taichung, Taiwan, ROC.
Che-Ming
CM
Liu
Chia-Ling
CL
Hsieh
Yun-Chi
YC
He
Sen-Jei
SJ
Lo
Ji-An
JA
Liang
Teng-Fu
TF
Hsieh
Sajni
S
Josson
Leland W K
LW
Chung
Mien-Chie
MC
Hung
Shian-Ying
SY
Sung
D051722:ADAM Proteins / Q000172:deficiency / Q000235:genetics*; D000728:Androgens / Q000378:metabolism; D000818:Animals; D001859:Bone Neoplasms / Q000503:physiopathology / Q000556:secondary; D002453:Cell Cycle / Q000235:genetics*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D059585:G1 Phase Cell Cycle Checkpoints / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D055785:Gene Knockdown Techniques; D020868:Gene Silencing; D015316:Genetic Therapy; D006801:Humans; D037181:Lectins, C-Type / Q000378:metabolism*; D016086:Lentivirus / Q000235:genetics*; D008297:Male; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics*; D051379:Mice; D058990:Molecular Targeted Therapy; D010014:Osteolysis / Q000235:genetics; D000073718:Pancreatitis-Associated Proteins; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology* / Q000628:therapy; D034741:RNA, Small Interfering / Q000235:genetics*; D059807:S Phase Cell Cycle Checkpoints / Q000235:genetics
D000728:Androgens; D037181:Lectins, C-Type; D008565:Membrane Proteins; D000073718:Pancreatitis-Associated Proteins; C428528:REG4 protein, human; D034741:RNA, Small Interfering; D051722:ADAM Proteins; C098339:ADAM9 protein, human