Department of Molecular Microbiology and Immunology, USC Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America.
PLoS One. 2011 Jan 18;6(1):e16205. doi: 10.1371/journal.pone.0016205.
Despite its initial positive response to hormone ablation therapy, prostate cancers invariably recur in more aggressive, treatment resistant forms. The lack of our understanding of underlying genetic alterations for the transition from androgen-dependent (AD) to ADI prostate cancer growth hampers our ability to develop target-driven therapeutic strategies for the efficient treatment of ADI prostate cancer.
METHODOLOGY/PRINCIPAL FINDINGS: By screening a library of activated human kinases, we have identified TPL2, encoding a serine/threonine kinase, as driving ADI prostate cancer growth. TPL2 activation by over-expressing either wild-type or a constitutively activated form of TPL2 induced ADI growth, whereas the suppression of TPL2 expression and its kinase activity in ADI prostate cancer cells inhibited cell proliferation under androgen-depleted conditions. Most importantly, TPL2 is upregulated in ADI prostate cancers of both the Pten deletion mouse model and the clinical prostate cancer specimens.
CONCLUSIONS/SIGNIFICANCE: Together these data suggest that TPL2 kinase plays a critical role in the promotion of ADI prostate cancer progression. Furthermore, the suppression of TPL2 diminishes ADI prostate cancer growth and a high frequency of TPL2 overexpression in human ADI prostate cancer samples validates TPL2 as a target for the treatment of this deadly disease.
尽管前列腺癌最初对激素消融疗法有积极反应，但它总是会以更具侵袭性和耐药性的形式复发。我们对雄激素依赖性（AD）向 ADI 前列腺癌生长转变的潜在遗传改变缺乏了解，这阻碍了我们开发针对 ADI 前列腺癌的靶向治疗策略的能力，从而无法有效治疗这种疾病。
方法/主要发现：通过筛选激活的人类激酶文库，我们鉴定出编码丝氨酸/苏氨酸激酶的 TPL2 可驱动 ADI 前列腺癌生长。过表达野生型或组成性激活形式的 TPL2 可激活 TPL2，从而诱导 ADI 生长，而在雄激素耗竭条件下抑制 ADI 前列腺癌细胞中 TPL2 的表达及其激酶活性则会抑制细胞增殖。最重要的是，TPL2 在 Pten 缺失小鼠模型和临床前列腺癌标本的 ADI 前列腺癌中均上调。
结论/意义：这些数据表明 TPL2 激酶在促进 ADI 前列腺癌进展中起关键作用。此外，抑制 TPL2 可减少 ADI 前列腺癌的生长，并且 TPL2 在人类 ADI 前列腺癌样本中的高表达频率验证了 TPL2 是治疗这种致命疾病的靶标。
