CDKs are attractive targets for the development of anticance

CDKs are attractive targets for the development of anticancer therapeutics, and inhibition of CDKs in malignant Alexidine dihydrochloride provides a promising approach in the defense against cancer [[24], [25], [26], [27]]. Recently, many selective CDK inhibitors targeting specific CDKs have been developed, which represent promising anti-cancer agents due to their strong anti-proliferative efficacy combined with a relative low direct cytotoxicity [[28], [29], [30], [31]]. Notably, palbociclib (IBRANCE®), a dual CDK4/6 inhibitor, recently received accelerated approval by the Food and Drug Administration (FDA) for breast cancer treatment due to its potent and selective inhibitory effect on estrogen receptor (ER) positive/human epidermal growth factor receptor 2 (HER2) negative breast cancer [[32], [33], [34]]. Furthermore, palbociclib has also been used in phase II clinical trial for liposarcoma therapy [35,36]. However, the expression and clinical significance of CDK4, and the potentials of targeting CDK4 as a putative therapeutic strategy in osteosarcoma are unclear.
Materials and methods
Results
Discussion CDK4 has been identified recently as a potential therapeutic target in human breast cancer, liposarcoma, melanoma, and glioblastoma [[37], [38], [39]]. Due to the importance of CDK4 activity in cancer cells, CDK4 inhibitors have emerged as promising candidates for the treatment of many cancer types [11]. In the current study, we aimed to explore the expression and the therapeutic potentials of CDK4 in osteosarcoma. We first determined CDK4 expression in both osteosarcoma tissues and cell lines and found CDK4 was highly expressed in most of the tested osteosarcoma tissue samples and in all the human osteosarcoma cell lines. These results suggest that CDK4 may be a critical player in osteosarcoma growth and proliferation. We further explored the relationship between CDK4 expression and the clinicopathological characteristics of osteosarcoma by using TMA containing 72 tissue samples from 54 osteosarcoma patients with complete clinical information, as well as up to 252 months of follow-up data. Our results showed that CDK4 expression significantly correlated with the metastasis status and clinical prognosis of osteosarcoma patients. Previously, CDK4 amplification has been found associated with a poor prognosis in liposarcoma patients [40]. Ewing sarcoma cells also require CDK4 for survival and anchorage-independent growth. Knockdown of CDK4 abrogated proliferation and transformation of fusion-gene positive rhabdomyosarcoma cells via G1 phase cell cycle arrest [41]. More recently, overexpression and activation of the CDK4/6 and Rb pathways have been found in chordoma, another rare type of sarcoma [42]. These findings together support that CDK4 plays important role in the development and progression in different sarcomas including osteosarcoma. Subsequently, we explored the functional roles of CDK4 in osteosarcoma cell proliferation and growth in vitro. We first inhibited CDK4 in osteosarcoma cells by the clinically approved CDK4 inhibitor palbociclib and investigated the cellular phenotypic alternations. Our findings demonstrated that CDK4 inhibition by palbociclib decreased osteosarcoma cell proliferation and growth in a dose-dependently manner, but exhibited only mild inhibition on CDK4-lower expressed NHOst cells. We further specifically knocked down CDK4 expression using CDK4 specific siRNA and determined osteosarcoma cell viability. Consistently, CDK4 inhibition by siRNA reduced osteosarcoma cell growth dose-dependently. These studies collectively suggest that CDK4 plays a crucial role in osteosarcoma proliferation and growth.