RNA interference-directed caveolin-1 knockdown sensitizes SN12CPM6 cells to doxorubicin-induced apoptosis and reduces lung metastasis.
Human renal cell carcinoma (HRCC) is characterized by a high level of resistance to all treatment modalities. Therefore, the investigation of global gene expression in HRCC might help understand its biologic behavior and develop treatment strategies. Using cDNA microarray analysis, we initially compared gene expression profiles between HRCCs and adjacent normal tissues, and found that 87 were up-regulated and 127 genes were down-regulated. Next, a subset of genes, twofold differentially expressed, were validated by Northern blotting. Unexpectedly, caveolin-1, a gene reported to be a tumor suppressor gene, was found to be up-regulated in HRCC tissues. Expression level of caveolin-1 in SN12CPM6 (high metastatic clone) was higher than in SN12C (low metastatic clone), and SN12CPM6 was more resistant to doxorubicin (DXR) than SN12C. Caveolin-1 gene was slightly induced in surviving SN12C cells after DXR treatment. Furthermore, SN12CPM6-siCav1 cells, which were transfected with siRNA of cavelon-1 gene, were more sensitive to DXR, compared to SN12CPM6, but reduction of caveolin-1 gene expression did not affect tumor formation in subcapsule of kidney and lung metastasis. On the other hand, induction of caveolin-1 gene affected the production of lung metastasis under anti-cancer drug treatment: the incidence of pulmonary metastasis was significantly lower in SCID mice injected with SN12CPM6-siCav1 cells, and the number of pulmonary nodules decreased significantly (p = 0.0004). The above results together suggest that caveolin-1 may confer a growth advantage to cancer cells during DXR chemotherapy and surviving HRCC cells eventually might develop lung metastasis.
Park
Juwon
J
Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea.
Bae
Eunkyung
E
Lee
Chansu
C
Yoon
Sung-Soo
SS
Chae
Yang Seok
YS
Ahn
Kwang-Sung
KS
Won
Nam Hee
NH
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D002292:Carcinoma, Renal Cell / Q000378:metabolism / Q000473:pathology*; D051242:Caveolin 1 / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000187:drug effects; D004317:Doxorubicin / Q000494:pharmacology*; D006801:Humans; D007680:Kidney Neoplasms / Q000378:metabolism / Q000473:pathology*; D008175:Lung Neoplasms / Q000517:prevention & control* / Q000556:secondary; D051379:Mice; D008819:Mice, Nude; D016513:Mice, SCID; D009362:Neoplasm Metastasis / Q000517:prevention & control; D034622:RNA Interference / Q000502:physiology*; D034741:RNA, Small Interfering / Q000235:genetics; D014162:Transfection; D014183:Transplantation, Heterologous; D015854:Up-Regulation / Q000187:drug effects
D000903:Antibiotics, Antineoplastic; D051242:Caveolin 1; D034741:RNA, Small Interfering; D004317:Doxorubicin
Cancer Res. 1997 Nov 15;57(22):5189-95
9371523
Surg Today. 2003;33(7):486-90
14506991
J Biol Chem. 1998 Dec 4;273(49):32380-3
9829965
J Urol. 2006 Jun;175(6):2302-6
16697863
Urol Res. 2000 Apr;28(2):86-92
10850629
APMIS. 2009 Jul;117(7):477-87
19594487
J Urol. 1990 Sep;144(3):755-9
1974934
Cancer Biol Ther. 2004 Oct;3(10):931-41
15539932
J Biol Chem. 2004 Oct 1;279(40):42270-8
15263006
J Bone Miner Res. 2007 Jan;22(1):37-44
17032147
Anticancer Drugs. 2003 Apr;14(4):281-7
12679732
Br J Cancer. 2004 Aug 31;91(5):959-65
15305200
Clin Cancer Res. 1998 Aug;4(8):1873-80
9717814
Clin Cancer Res. 2004 Sep 15;10(18 Pt 2):6315S-21S
15448024
Cancer Res. 2001 Jun 1;61(11):4386-92
11389065
Oncogene. 1997 Nov 27;15(22):2727-33
9400999
J Nephrol. 2009 Nov-Dec;22(6):708-15
19967649
Br J Cancer. 2003 Nov 17;89(10):1909-13
14612902
BJU Int. 2004 Feb;93(3):291-6
14764125
Curr Opin Cell Biol. 1996 Aug;8(4):542-8
8791446
Lung Cancer. 2008 Jan;59(1):105-10
17850918
Cancer Biol Ther. 2004 Oct;3(10):954-9
15326378
Oncogene. 1998 Mar;16(11):1391-7
9525738
World J Urol. 1994;12(4):214-23
7820144
Am J Pathol. 2002 Nov;161(5):1647-56
12414512
J Biol Chem. 2000 Jul 7;275(27):20847-52
10781609
J Biol Chem. 2005 Jul 1;280(26):25134-45
15802273
Mol Immunol. 2010 Feb;47(5):1047-57
20004976