Chronic solar ultraviolet exposure is a major risk factor for cutaneous squamous cell carcinoma (cSCC), which is the second most common type of skin cancer. Our previous data showed that total protein and phosphorylation levels of T-LAK cell-originated protein kinase (TOPK) were enhanced in solar-simulated light (SSL)-induced skin carcinogenesis and overexpressed in actinic keratosis (AK) and cSCC human skin tissues compared to those in matched normal skin. Thus, targeting TOPK activity could be a helpful approach for treating cSCC. Our data showed that orobol directly binds to TOPK in an ATP-independent manner and inhibits TOPK kinase activity. Furthermore, orobol inhibited anchorage-independent colony formation by SCC12 cells in a dose-dependent manner. After discontinuing the treatment, patients commonly return to tumor-bearing conditions; therefore, therapy or intermittent dosing of drugs must be continued indefinitely. Thus, to examine the efficacy of orobol against the development and regrowth of cSCC, we established mouse models including prevention, and therapeutic models on the chronic SSL-irradiated SKH-1 hairless mice. Early treatment with orobol attenuates chronic SSL-induced cSCC development. Furthermore, orobol showed therapeutic efficacy after the formation of chronic SSL irradiation-induced tumor. In the mouse model with intermittent dosing of orobol, our data showed that re-application of orobol is effective for reducing tumor regrowth after discontinuation of treatment. Moreover, oncogenic protein levels were significantly attenuated by orobol treatment in the SSL-stimulated human skin. Thus, we suggest that orobol, as a promising TOPK inhibitor, could have an effective clinical approach to prevent and treat the development and regrowth of cSCC.
Bibliographical noteFunding Information:
We thank Tara J. Adams and Kjersten Monson (SURE intern) for assisting in animal studies. This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (2019R1C1C1004387), Regional Innovation Strategy (RIS) through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (MOE) (2021RIS-001), the Korea Technology and Information Promotion Agency for SMEs (TIPA) grant funded by the Korea government (Ministry of SMEs and Startups, Republic of Korea) (No. S3174595) and Korea National University of Transportation in 2022. This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (2022R1F1A1074895).
- Skin carcinogenesis
- Solar-simulated light
- Squamous cell carcinoma
- UV radiation
PubMed: MeSH publication types
- Journal Article
- Research Support, Non-U.S. Gov't