p53R2 is a prognostic factor of melanoma and regulates proliferation and chemosensitivity of melanoma cells.
BACKGROUND
The treatment of melanoma, an aggressive, chemo-resistant skin cancer characterized by rapid metastasis and a poor prognosis, requires the development of innovative therapies with improved efficacy. The p53R2 gene that encodes the ribonucleotide reductase small subunit 2 homologue is induced by several stress signals including DNA-damaging agents that activate p53. The p53R2 gene product increases the deoxynucleotide triphosphate pool in the nucleus; this facilitates DNA repair and synthesis.


OBJECTIVE
We examined the expression of p53R2 in melanoma and evaluated whether p53R2 is involved in the growth and proliferation of melanoma cells. Methods We examined the clinicopathological significance of p53R2 in melanoma. To investigate the role of p53R2 in melanoma we used KHm5 and KHm6 melanoma cells that express p53R2, and p53R2-targeting small interfering (si) RNA.


RESULTS
p53R2 expression was detected immunohistochemically in 56 of 78 patients (71.8%). The expression of p53R2 was significantly correlated with the depth of invasion and the tumor stage. p53R2-targeting siRNA successfully knocked down p53R2 and significantly inhibited the growth of KHm5 and 6 cells. Moreover, The degree of KHm5 and 6 cell growth inhibition was greater in the presence of both p53R2-targeting siRNA and nimustine (ACNU) than with ACNU alone, suggesting that p53R2 silencing enhanced the chemosensitivity of KHm5 and 6 cells to ACNU.


CONCLUSIONS
We propose p53R2 as a therapeutic target to enhance the effectiveness of chemotherapy in patients with p53R2-positive melanoma.
Department of Dermatology, Field of Sensory Organology, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8520, Japan. shige@m2.kufm.kagoshima-u.ac.jp
Shigeto
S
Matsushita
Ryuji
R
Ikeda
Tomoko
T
Fukushige
Yusuke
Y
Tajitsu
Kanayo
K
Gunshin
Hiroshi
H
Okumura
Mina
M
Ushiyama
Shin-ichi
S
Akiyama
Kazuhiro
K
Kawai
Yasuo
Y
Takeda
Katsushi
K
Yamada
Takuro
T
Kanekura
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000494:pharmacology*; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002648:Child; D002945:Cisplatin / Q000494:pharmacology; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D003606:Dacarbazine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008545:Melanoma / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D015376:Nimustine / Q000494:pharmacology; D011379:Prognosis; D034622:RNA Interference; D012264:Ribonucleotide Reductases / Q000235:genetics / Q000378:metabolism*; D012878:Skin Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D014162:Transfection; D014750:Vincristine / Q000494:pharmacology; D055815:Young Adult
D000970:Antineoplastic Agents; C493956:CDKN1A protein, human; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D015376:Nimustine; D014750:Vincristine; D003606:Dacarbazine; C405947:RRM2B protein, human; D012264:Ribonucleotide Reductases; D002945:Cisplatin