Inhibition of Polo-like kinase 4 induces mitotic defects and DNA damage in diffuse large B-cell lymphoma

Abstract

Polo-like kinase 4 (PLK4), a key regulator of centriole biogenesis, has recently been shown to play key roles in tumorigenesis. Blocking PLK4 expression by interference or targeted drugs exhibits attractive potential in improving the efficacy of chemotherapy. Nevertheless, the role of PLK4 in diffuse large B-cell lymphoma (DLBCL) is still undefined. In this study, we discover that PLK4 is a potential target for the treatment of DLBCL, and demonstrate the efficacy of a PLK4 inhibitor when used in combination with doxorubicin. Pharmaceutical inhibition of PLK4 with CFI-400945 inhibited DLBCL cell proliferation and induced apoptotic cell death. The anti-tumor effects were accompanied by mitotic defects, including polyploidy and cytokinesis failure. Activation of p53 and Hippo/YAP tumor suppressor signaling pathway was identified as the potential mechanisms driving CFI-400945 activity. Moreover, CFI-400945 treatment resulted in activation of DNA damage response. Combining CFI-400945 with doxorubicin markedly delayed tumor progression in DLBCL xenografts. Finally, PLK4 was increased in primary DLBCL tissues and cell lines. High levels of PLK4 expression were associated with poor survival in the patients receiving CHOP-based treatment, implicating PLK4 as a predictive biomarker of DLBCL chemosensitivity. These results provide the therapeutic potential of CFI-400945 both as monotherapy or in combination with doxorubicin for the treatment of DLBCL.

Downregulation of PLK4 expression induces apoptosis and G0/G1‐phase cell cycle arrest in keloid fibroblasts

“…Although PLK4 was shown to be aberrantly expressed in many tumor types in the recently published literature, it is also expressed at low levels in proliferative tissues, such as the pancreas and skin 20,21 . In the present study, we found that keloids, which are considered dermal fibroproliferative tumors, exhibited higher mRNA and protein levels of PLK4 in the dermal layer, especially in the superficial dermis, than in their corresponding adjacent normal skin tissues.…”

“…Keloids represent benign fibroproliferative skin tumors that display many cancer‐like characteristics, such as progressive uncontrolled growth, lack of spontaneous regression, and extremely high rates of recurrence. PLK4 has been identified as a causative factor for the development of various tumors 13–18 and proliferative tissues 19–21 . However, to the best of our knowledge, no study has investigated its role in keloids.…”

“…The PLK4 enzyme is expressed at low levels in proliferating tissues and has pleiotropic functions in processes related to mitotic progression, including cytokinesis, cell mobility, and DNA damage repair 11,12 . Increasing evidence indicates that PLK4 is aberrantly expressed in patient‐derived tumor samples, including colorectal cancer, 13,14 breast cancer, 15,16 bladder cancer, 17 and melanoma, 18 but is also expressed at low levels in proliferative tissues 19–21 . However, its expression level differs among cancers and proliferative tissues.…”

“… 11 , 12 Increasing evidence indicates that PLK4 is aberrantly expressed in patient‐derived tumor samples, including colorectal cancer, 13 , 14 breast cancer, 15 , 16 bladder cancer, 17 and melanoma, 18 but is also expressed at low levels in proliferative tissues. 19 , 20 , 21 However, its expression level differs among cancers and proliferative tissues. Moreover, high expression of PLK4 endows cancer cells with invasive and metastatic abilities.…”

“…is also expressed at low levels in proliferative tissues. [19][20][21] However, its expression level differs among cancers and proliferative tissues.…”