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CX-F9, a novel RSK2 inhibitor, suppresses cutaneous melanoma cells proliferation and metastasis through regulating autophagy.

Abstract

Approximately 60% of melanoma have BRAF mutation which leads to the abnormal activation of MAPK signaling pathway. Therefore, targeting these signaling pathways is particularly important for melanoma therapy. Ribosomal S6 Kinase 2 (RSK2) is a downstream target of ERK1/2 in MAPK/ERK pathway and inhibition of RSK2 suppresses the tumorigenesis and metastasis of neoplasm. We investigated whether CX-F9, a novel RSK2 inhibitor predicted by computer, inhibits the malignant phenotype of melanoma cells. In this study, we found knockdown of RSK2 expression in melanoma cells induces autophagy and inhibits its proliferation, migration and invasion. CX-F9 directly binds to RSK2 and inhibits the kinase activity. CX-F9 significantly suppressed cell proliferation, induced autophagy, apoptosis and cycle arrest, as well as inhibited migration and invasion in SK-MEL-5 and SK-MEL-28 cells. Western blotting revealed that CX-F9 declined the activation of p-CREB. Moreover, CX-F9 inhibited tumor formation and metastasis in vivo. Furthermore, CX-F9 suppressed cell proliferation, migration, invasion in BRAF inhibitor resistant melanoma cells. These findings reveal a new RSK2 inhibitor CX-F9 could significantly suppressed malignant phenotype of melanoma in vitro and in vivo, which provide a novel strategy for melanoma treatment in clinic.

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  • Authors+Show Affiliations

    ,

    The Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan, China; Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha, Hunan, China; Hunan Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Central South University, Changsha, Hunan, China.

    ,

    The Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan, China; Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha, Hunan, China; Hunan Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Central South University, Changsha, Hunan, China.

    ,

    The Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan, China; Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha, Hunan, China; Hunan Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Central South University, Changsha, Hunan, China.

    ,

    The Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan, China; Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha, Hunan, China; Hunan Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Central South University, Changsha, Hunan, China.

    ,

    The Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan, China; Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha, Hunan, China; Hunan Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Central South University, Changsha, Hunan, China.

    ,

    The Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan, China; Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha, Hunan, China; Hunan Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Central South University, Changsha, Hunan, China.

    ,

    The Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan, China; Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha, Hunan, China; Hunan Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Central South University, Changsha, Hunan, China.

    ,

    The Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan, China; Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha, Hunan, China; Hunan Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Central South University, Changsha, Hunan, China.

    ,

    Department of Dermatology, Affiliated Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

    ,

    Department of Plastic Surgery of Third Xiangya Hospital, Central South University, Changsha, China.

    ,

    The Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan, China; Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha, Hunan, China; Hunan Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Central South University, Changsha, Hunan, China. Electronic address: chenxiangck@126.com.

    The Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan, China; Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha, Hunan, China; Hunan Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Central South University, Changsha, Hunan, China. Electronic address: pengcongxy@csu.edu.cn.

    Source

    Biochemical pharmacology 168: 2019 Jun 14 pg 14-25

    Pub Type(s)

    Journal Article

    Language

    eng

    PubMed ID

    31207212

    Citation

    Zhang, Xu, et al. "CX-F9, a Novel RSK2 Inhibitor, Suppresses Cutaneous Melanoma Cells Proliferation and Metastasis Through Regulating Autophagy." Biochemical Pharmacology, vol. 168, 2019, pp. 14-25.
    Zhang X, Cai L, Zhao S, et al. CX-F9, a novel RSK2 inhibitor, suppresses cutaneous melanoma cells proliferation and metastasis through regulating autophagy. Biochem Pharmacol. 2019;168:14-25.
    Zhang, X., Cai, L., Zhao, S., Long, J., Li, J., Wu, L., ... Peng, C. (2019). CX-F9, a novel RSK2 inhibitor, suppresses cutaneous melanoma cells proliferation and metastasis through regulating autophagy. Biochemical Pharmacology, 168, pp. 14-25. doi:10.1016/j.bcp.2019.06.014.
    Zhang X, et al. CX-F9, a Novel RSK2 Inhibitor, Suppresses Cutaneous Melanoma Cells Proliferation and Metastasis Through Regulating Autophagy. Biochem Pharmacol. 2019 Jun 14;168:14-25. PubMed PMID: 31207212.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - CX-F9, a novel RSK2 inhibitor, suppresses cutaneous melanoma cells proliferation and metastasis through regulating autophagy. AU - Zhang,Xu, AU - Cai,Lei, AU - Zhao,Shuang, AU - Long,Jing, AU - Li,Jie, AU - Wu,Lisha, AU - Su,Juan, AU - Zhang,JiangLing, AU - Tao,Juan, AU - Zhou,Jianda, AU - Chen,Xiang, AU - Peng,Cong, Y1 - 2019/06/14/ PY - 2019/05/04/received PY - 2019/06/12/accepted PY - 2019/6/18/pubmed PY - 2019/6/18/medline PY - 2019/6/18/entrez KW - Autophagy KW - CX-F9 KW - Cancer therapeutics KW - Melanoma KW - RSK2 SP - 14 EP - 25 JF - Biochemical pharmacology JO - Biochem. Pharmacol. VL - 168 N2 - Approximately 60% of melanoma have BRAF mutation which leads to the abnormal activation of MAPK signaling pathway. Therefore, targeting these signaling pathways is particularly important for melanoma therapy. Ribosomal S6 Kinase 2 (RSK2) is a downstream target of ERK1/2 in MAPK/ERK pathway and inhibition of RSK2 suppresses the tumorigenesis and metastasis of neoplasm. We investigated whether CX-F9, a novel RSK2 inhibitor predicted by computer, inhibits the malignant phenotype of melanoma cells. In this study, we found knockdown of RSK2 expression in melanoma cells induces autophagy and inhibits its proliferation, migration and invasion. CX-F9 directly binds to RSK2 and inhibits the kinase activity. CX-F9 significantly suppressed cell proliferation, induced autophagy, apoptosis and cycle arrest, as well as inhibited migration and invasion in SK-MEL-5 and SK-MEL-28 cells. Western blotting revealed that CX-F9 declined the activation of p-CREB. Moreover, CX-F9 inhibited tumor formation and metastasis in vivo. Furthermore, CX-F9 suppressed cell proliferation, migration, invasion in BRAF inhibitor resistant melanoma cells. These findings reveal a new RSK2 inhibitor CX-F9 could significantly suppressed malignant phenotype of melanoma in vitro and in vivo, which provide a novel strategy for melanoma treatment in clinic. SN - 1873-2968 UR - https://www.unboundmedicine.com/medline/citation/31207212/CX-F9,_a_Novel_RSK2_Inhibitor,_suppresses_Cutaneous_Melanoma_Cells_Proliferation_and_Metastasis_through_regulating_Autophagy L2 - https://linkinghub.elsevier.com/retrieve/pii/S0006-2952(19)30233-3 DB - PRIME DP - Unbound Medicine ER -