A novel ribosomal protein S6 kinase 2 inhibitor attenuates the malignant phenotype of cutaneous malignant melanoma cells by inducing cell cycle arrest and apoptosis

Yayun Li; Pian Yu; Jing Long; Ling Tang; Xu Zhang; Zhe Zhou; DongSheng Cao; Juan Su; Xiang Chen; Cong Peng

doi:10.1080/21655979.2022.2080364

A novel ribosomal protein S6 kinase 2 inhibitor attenuates the malignant phenotype of cutaneous malignant melanoma cells by inducing cell cycle arrest and apoptosis

Bioengineered. 2022 May;13(5):13555-13570. doi: 10.1080/21655979.2022.2080364.

Authors

Yayun Li^{1

2

3}, Pian Yu^{1

2

3}, Jing Long^{1

2

3}, Ling Tang^{1

2

3}, Xu Zhang^{1

2

3}, Zhe Zhou^{1

2

3}, DongSheng Cao⁴, Juan Su^{1

2

3}, Xiang Chen^{1

2

3}, Cong Peng^{1

2

3}

Affiliations

¹ Department of Dermatology, Hunan Engineering Research Center of Skin Health and Disease, Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Clinical Research Center for Cancer Immunotherapy, Xiangya Hospital, Central South University, Changsha, Hunan, China.
² National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology, Central South University, Changsha, Hunan, China.
³ National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China.
⁴ Hunan Key Laboratory of Processed Food for Special Medical Purpose, Central South University of Forestry and Technology, Hunan, China.

Abstract

Malignant melanoma (MM) is a highly life-threatening tumor causing the majority of the cutaneous cancer-related deaths. Previously, ribosomal protein S6 kinase 2 (RSK2), the downstream effector of the MAPK pathway, represents a therapeutic target in melanoma. AE007 is discovered as a targeted RSK2 inhibitor, and subsequent results showed that AE007 inhibits RSK2 by directly binding to its protein kinase domain. AE007 causes cell cycle arrest and cellular apoptosis, thereby dramatically inhibiting proliferation, migration, and invasion of melanoma cells. Nevertheless, melanocytes and keratinocytes are not affected by this compound. In addition, suppression of RSK2 abrogates the inhibitory effect of AE007 on melanoma cell proliferation. AE007 treatment significantly inhibits the expression of Cyclin D1, Cyclin B1, CDK2, and Bcl-2, while raises the cleavage of PARP. Moreover, RNA sequencing results show that AE007 treatment can affect the genes expression profile, including the expression of cell cycle and DNA replication genes. In conclusion, AE007 is a promising melanoma therapeutic agent by targeting RSK2.

Keywords: AE007; Melanoma; RSK2; apoptosis; cell cycle arrest.

MeSH terms

Apoptosis*
Cell Cycle
Cell Cycle Checkpoints*
Cell Line, Tumor
Humans
Melanoma* / drug therapy
Melanoma* / genetics
Melanoma* / metabolism
Melanoma, Cutaneous Malignant
Ribosomal Protein S6 Kinases, 90-kDa* / antagonists & inhibitors

Substances

ribosomal protein S6 kinase, 90kDa, polypeptide 3
Ribosomal Protein S6 Kinases, 90-kDa

Grants and funding

This work was supported by the National Natural Science Foundation of China, Grant No. 82073458 (Cong Peng), 81830096 (Xiang Chen), 8213000715 (Xiang Chen).