PRIMA-1Met/APR-246 induces wild-type p53-dependent suppression of malignant melanoma tumor growth in 3D culture and in vivo.
Disseminating malignant melanoma is a lethal disease highly resistant to radio- and chemotherapy. Therefore, the development of new treatment strategies is strongly needed. Tumor suppressor p53-mediated apoptosis is essential for the response to radio- and chemotherapy. Although p53 is not frequently mutated in melanoma, it is inactivated by integrin αv-mediated signaling, as we previously demonstrated 1, which may account, at least partially, for increased apoptosis resistance of malignant melanoma. In this study we addressed the question whether functional restoration of p53 by APR-246 (PRIMA-1Met), which can reactivate mutant p53 and induce massive apoptosis in cancer cells, is able to restore the function of inactive p53 in melanoma. Using a three-dimensional collagen gel (3D-collagen) to culture melanoma cells carrying wild-type p53, we found that APR-246 treatment resulted in activation of p53, leading to increased expression of p53 pro-apoptotic targets Apaf1 and PUMA and activation of caspase- 9 and -3. Moreover, APR-246 triggered melanoma cell apoptosis that was mediated by p53 and caspase 9. Importantly, APR-246 treatment also suppressed human melanoma xenograft tumors in vivo in a p53-dependent manner. Thus, wild-type p53 reactivation may provide a novel approach for malignant melanoma treatment, with APR-246 as a candidate drug for such a development.
Department of Laboratory Medicine, Karolinska Institutet, Huddinge, Sweden.
Wenjie
W
Bao
Ming
M
Chen
Xu
X
Zhao
Ravjiv
R
Kumar
Clemens
C
Spinnler
Minna
M
Thullberg
Natalia
N
Issaeva
Galina
G
Selivanova
Staffan
S
Strömblad
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D053477:Apoptotic Protease-Activating Factor 1 / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D018929:Cell Culture Techniques; D045744:Cell Line, Tumor; D006801:Humans; D008545:Melanoma / Q000188:drug therapy* / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D011812:Quinuclidines / Q000627:therapeutic use*; D034622:RNA Interference; D034741:RNA, Small Interfering; D014183:Transplantation, Heterologous; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism* / Q000502:physiology
C506592:APAF1 protein, human; D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D053477:Apoptotic Protease-Activating Factor 1; C438378:BBC3 protein, human; D011518:Proto-Oncogene Proteins; D011812:Quinuclidines; D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53; D053148:Caspase 3; D053453:Caspase 9; C533410:eprenetapopt