Lee Ji-Hae, Lee Ji-Yeon, Rho Seung Bae, Choi Jong-Soon, Lee Dong-Gi, An Sungwhan, Oh Taejeong, Choi Don-Chan, Lee Seung-Hoon
Department of Life Science, YongIn University, 470 Samga-dong Chuingu, Yonginsi, South Korea; Research Institute, National Cancer Center, Ilsandong-gu, Goyang-si, Gyeonggi-do, South Korea.
Research Institute, National Cancer Center, Ilsandong-gu, Goyang-si, Gyeonggi-do, South Korea.
FEBS Lett. 2014 Dec 20;588(24):4730-9. doi: 10.1016/j.febslet.2014.11.004. Epub 2014 Nov 15.
Secretory clusterin (sCLU), an anti-apoptotic protein, is overexpressed in many tumors and enhances tumorigenesis and chemo-resistance. However, the regulation mechanism controlling the sCLU maturation process or activity remains undetermined. In this study, we found PACAP as a negative regulator of CLU. Overexpression of the PACAP gene in cervical cancer cell lines lacking PACAP expression significantly inhibited cell growth and induced apoptosis. We further demonstrated that interaction of PACAP with CLU significantly downregulated CLU expression and secretion, inhibited the Akt-Raf-ERK pathway, and suppressed the growth of human tumor xenografts in nude mice. This novel inhibitory function of PACAP may be applicable for developing novel molecular therapies for tumors with increased sCLU expression.
分泌型簇集蛋白（sCLU）是一种抗凋亡蛋白，在许多肿瘤中过度表达，可促进肿瘤发生和化疗耐药性。然而，控制sCLU成熟过程或活性的调控机制仍未明确。在本研究中，我们发现垂体腺苷酸环化酶激活肽（PACAP）是CLU的负调控因子。在缺乏PACAP表达的宫颈癌细胞系中过表达PACAP基因可显著抑制细胞生长并诱导凋亡。我们进一步证明，PACAP与CLU的相互作用显著下调CLU的表达和分泌，抑制Akt-Raf-ERK通路，并抑制裸鼠体内人肿瘤异种移植瘤的生长。PACAP的这种新的抑制功能可能适用于开发针对sCLU表达增加的肿瘤的新型分子疗法。
