Development of molecular target-based therapy of cutaneous squamous cell carcinoma by selective block of PI3K isoforms

磷酸肌醇3-激酶（PI 3 K）是调节广泛的细胞过程的脂质激酶家族，其中包括细胞存活、生长和增殖，这些过程的失调导致癌症。PI 3 K I类家族有4个成员，其中催化亚基为p110 α、p110 β、p110 γ和p110 δ亚型，为了揭示其在癌症发生中的作用，我们检测了缺失PI 3 K各种亚型的影响（p85α、p110 α、p110 γ和p110 δ）对PTEN-/-小鼠中上皮肿瘤的影响。我们发现p110α的杂合性缺失或p110 γ的纯合性缺失均导致上皮性肿瘤的发生率增加。这些结果表明，降低不同p110亚基的水平可导致表皮中PI 3 K信号转导的降低，支持p110α和p110 γ两者在一些组织中可作为PI 3 K信号转导的抑制剂起作用并因此抑制肿瘤形成的模型。我们的结果表明p110α和p110 γ在介导PTEN-/-小鼠上皮肿瘤病变中的PI 3 K信号传导中起关键作用，针对癌症中PI 3 K途径的治疗方法可以利用这些亚型之间的差异。

Phosphoinositide 3-kinases (PI3Ks) are a family of lipid kinases that regulate a wide range of cellular processes, among which are cell survival, growth, and proliferation, processes whose misregulation contributes to cancer. There are 4 members in the PI3K class I family, in which the catalytic subunits are p 110α, p 110β, p 110γ, and p 110δ isoforms.To reveal its role in cancer development, we examined the effect of deleting various isoforms of PI3K (p85α, p 110α, p 110γ, and p 110δ) on epithelial neoplasma in PTEN-/-mice.Interestingly, we found that either the heterozygous loss of p110α or the homozygous loss of p 110γ led to ecreased incidence of epithelial neoplasma. These results indicate that decreasing the levels of different p 110 subunits can result in decreased PI3K signaling in epidermis, supporting the model that both p110α and p 110γ can function as inhibitors of PI3K signaling in some tissues and thus suppress tumor formation.Taken together, our results suggest that both the p110α and p 110γ play crucial roles in mediating PI3K signaling in epithelial neoplastic lesions in PTEN-/-mice, and therapeutic approaches that target the PI3K pathway in cancer may exploit such differences between these isoforms.