Chemical Oral Cancerogenesis Is Impaired in PI3Kγ Knockout and Kinase-Dead Mice

SIMPLE SUMMARY: Oral carcinoma remains one of the most challenging cancers to be cured and the pharmacological approach is often ineffective. The identification of novel molecular targets will greatly improve its management. We wondered if PI3Kγ might be looked at as a target in oral cancer handling. In this preclinical study, we analyzed the role of PI3Kγ in a murine transgenic model. We demonstrated that the absence/inhibition of PI3Kγ might be a reasonable strategy to impair the development of preneoplastic and neoplastic lesions of the oral cavity. PI3Kγ is not required for normal development, life span, or basic immune responses, unless under stress conditions; therefore, low toxicity and few side effects are expected by acting on PI3Kγ as a therapeutic target. ABSTRACT: We investigated the role of PI3Kγ in oral carcinogenesis by using a murine model of oral squamous carcinoma generated by exposure to 4-nitroquinoline 1-oxide (4NQO) and the continuous human cancer cell line HSC-2 and Cal-27. PI3Kγ knockout (not expressing PI3Kγ), PI3Kγ kinase-dead (carrying a mutation in the PI3Kγ gene causing loss of kinase activity) and wild-type (WT) C57Bl/6 mice were administered 4NQO via drinking water to induce oral carcinomas. At sacrifice, lesions were histologically examined and stained for prognostic tumoral markers (EGFR, Neu, cKit, Ki67) and inflammatory infiltrate (CD3, CD4, CD8, CD19 and CD68). Prevalence and incidence of preneoplastic and exophytic lesions were significantly and similarly delayed in both transgenic mice versus the control. The expression of prognostic markers, as well as CD19(+) and CD68(+) cells, was higher in WT, while T lymphocytes were more abundant in tongues isolated from transgenic mice. HSC-2 and Cal-27 cells were cultured in the presence of the specific PI3Kγ-inhibitor (IPI-549) which significantly impaired cell vitality in a dose-dependent manner, as shown by the MTT test. Here, we highlighted two different mechanisms, namely the modulation of the tumor-infiltrating cells and the direct inhibition of cancer-cell proliferation, which might impair oral cancerogenesis in the absence/inhibition of PI3Kγ.