Abstract
Mastl kinase promotes mitotic progression and cell cycle reentry after DNA damage. We report here that Mastl is frequently upregulated in various types of cancer. This upregulation was correlated with cancer progression in breast and oral cancer, poor patient survival in breast cancer, and tumor recurrence in head and neck squamous cell carcinoma. We further investigated the role of Mastl in tumor resistance using cell lines derived from the initial and recurrent tumors of the same head and neck squamous cell carcinoma patients. Ectopic expression of Mastl in the initial tumor cells strongly promoted cell proliferation in the presence of cisplatin by attenuating DNA damage signaling and cell death. Mastl knockdown in recurrent tumor cells re-sensitized their response to cancer therapy in vitro and in vivo. Finally, Mastl targeting specifically potentiated cancer cells to cell death in chemotherapy while sparing normal cells. Thus, this study revealed that Mastl upregulation is involved in cancer progression and tumor recurrence after initial cancer therapy, and validated Mastl as a promising target to increase the therapeutic window.
Highlights
Understanding the molecular mechanism of cancer progression is imperial to cancer prevention and early diagnosis
We analyzed the protein level of microtubuleassociated serine/threonine kinase like (Mastl) in a panel of head and neck squamous cell carcinoma (SCC) cell lines to determine if the level of Mastl is altered in cancer
In this study we showed that Mastl may act as a new oncogene in light of several lines of evidence
Summary
Understanding the molecular mechanism of cancer progression is imperial to cancer prevention and early diagnosis. Elucidating the cellular pathways that render tumor cells resistant to cancer treatment will propel the development of more effective cancer therapeutics. Plk, Aurora A, and Aurora B are serine/threonine kinases that regulate multiple aspects of mitotic progression. These kinases have been shown to be upregulated in various types of cancer, consistent with a large body of evidence that indicated the oncogenic activity of these kinases in established human cell lines and animal models. A number of small molecule inhibitors of Plk and Aurora kinases are under clinical development for cancer therapy [3]
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