Abstract
Osteosarcoma (OS) is a primary malignant bone neoplasm with high frequencies of tumor metastasis and recurrence. Although the Akt/PKB signaling pathway is known to play key roles in tumorigenesis, the roles of cyclin-dependent kinase-like 3 (CDKL3) in OS progression remain largely elusive. We have demonstrated the high expression levels of CDKL3 in OS human specimens and comprehensively investigated the role of CDKL3 in promoting OS progression both in vitro and in vivo. We found that CDKL3 regulates Akt activation and its downstream effects, including cell growth and autophagy. The up-regulation of CDKL3 in OS specimens appeared to be associated with Akt activation and shorter overall patient survival (P = 0.003). Our findings identify CDKL3 as a critical regulator that stimulates OS progression by enhancing Akt activation. CDKL3 represents both a biomarker for OS prognosis, and a potential therapeutic target in precision medicine by targeting CDKL3 to treat Akt hyper-activated OS.
Highlights
Osteosarcoma (OS) is the most common primary bone malignancy in children (Kansara, 2014; Reed et al, 2017)
Silencing of CDK6 and Cyclin-dependent kinase–like 3 (CDKL3) significantly inhibited the growth of U2OS cells compared with the control, with inhibitory rates of 30.49% ± 3.59% and 32.17% ± 3.61%, respectively (P < 0.001), whereas interfering expression of any other cyclin-dependent protein kinase–like (CDKL) did not affect the growth of U2OS cells (Fig 1B)
Together with prior literatures that alteration of Akt/mTOR signaling pathway was observed in OS (Bishop & Janeway, 2016; Sayles et al, 2019), our data moved it to a further step, demonstrating that CDKL3 may represent a potential targetable subclass of OS. We integrated both bench studies and bedside analyses to establish the oncogenic role of CDKL3 in OS progression
Summary
Osteosarcoma (OS) is the most common primary bone malignancy in children (Kansara, 2014; Reed et al, 2017). Advanced combinational therapies composed of intensive multidrug treatment and surgeries have been applied to treat OS, yet the 5-yr survival rate for patients with metastasis or relapse remains disappointing with a statistic of less than 30% (Kager et al, 2003; Mirabello et al, 2009). This stagnation of clinical consequences highlights the critical need for defining molecular mechanisms underlying OS development and exploring novel targeted biomarkers and therapies. A few studies have linked CDKL3 with cancers, the evidence is far lacking in solid support of its role and mechanisms underlying cancer progression (Ye et al, 2018; Zhang et al, 2018)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
