Inhibition of MARK2 inhibits ovarian cancer cell proliferation by regulating PI3K/AKT/p53 axis

Ovarian cancer (OC) is the 3rd most common type of the gynecological malignancy. Although current treatment strategies have greatly improved, there is still a need to develop new biomarkers for OC diagnosis and treatment. Microtubule affinity regulated kinase 2 (MARK2) is a kinase involved in the progression of multiple tumors. However, whether abnormal expression of MARK2 is associated with OC progression needs further analysis. We here revealed its role in OC. We found high expression of MARK2 in OC. Knockdown of MARK2 inhibited proliferation of OC cells, stimulated apoptosis of OC cells, and restrained glucose metabolism of OC cells. Furthermore, MARK2 regulated phosphatidylinositol 3-kinase/PKB (protein kinase B)/tumor suppressor protein 53 (PI3K/AKT/p53) axis in OC, therefore affecting the progression of OC. In summary, MARK2 knockdown suppressed cell proliferation by regulating PI3K/AKT/p53 axis.

Ovarian cancer (OC); Microtubule affinity regulated kinase 2 (MARK2); Apoptosis; glucose metabolism; PI3K/AKT/p53

[1] Chen X, Wu QS, Meng FC, Tang ZH, Chen X, Lin L, et al. Corrigendum: chikusetsusaponin IVa methyl ester induces G1 cell cycle arrest, triggers apoptosis and inhibits migration and invasion in ovarian cancer cells. Phytomedicine. 2016; 23: 1555–1565. Phytomedicine. 2017; 29: e1.

[2] Koyanagi T, Saga Y, Takahashi Y, Tamura K, Yoshiba T, Takahashi S, et al. Knockout of vasohibin-2 reduces tubulin carboxypeptidase activity and increases paclitaxel sensitivity in ovarian cancer. Cancer Medicine. 2021; 10: 2732–2739.

[3] Burnell M, Gentry-Maharaj A, Glazer C, Karpinskyj C, Ryan A, Apostolidou S, et al. Serial endometrial thickness and risk of non-endometrial hormone-dependent cancers in postmenopausal women in UK Collaborative Trial of Ovarian Cancer Screening. Ultrasound in Obstetrics & Gynecology. 2020; 56: 267–275.

[4] Wu ES, Barber EL, Dao MD, Zsiros E, Urban RR, Gray HJ, et al. Timing and duration of bevacizumab treatment and survival in patients with recurrent ovarian, fallopian tube, and peritoneal cancer: a multi-institution study. European Journal of Gynaecological Oncology. 2023; 44: 17–25.

[5] Huang X, Li XY, Shan WL, Chen Y, Zhu Q, Xia BR. Targeted therapy and immunotherapy: diamonds in the rough in the treatment of epithelial ovarian cancer. Frontiers in Pharmacology. 2023; 14: 1131342.

[6] Tang EI, Cheng CY. MARK2 and MARK4 regulate Sertoli cell BTB dynamics through microtubule and actin cytoskeletons. Endocrinology. 2022; 163: bqac130.

[7] Zuo YC, Xiong NX, Shen JY, Yu H, Huang YZ, Zhao HY. MARK2 rescues Nogo-66-induced inhibition of neurite outgrowth via regulating microtubule-associated proteins in neurons in vitro. Neurochemical Research. 2016; 41: 2958–2968.

[8] Hart M, Zulkipli I, Shrestha RL, Dang D, Conti D, Gul P, et al. MARK2/Par1b kinase present at centrosomes and retraction fibres corrects spindle off-centring induced by actin disassembly. Open Biology. 2019; 9: 180263.

[9] Hou S, Zhang X, Yang J. Long non-coding RNA ABHD11-AS1 facilitates the progression of cervical cancer by competitively binding to miR-330-5p and upregulating MARK2. Experimental Cell Research. 2022; 410: 112929.

[10] Xu G, Ge Y, Tao X, Gao Q, Liang X. MARK2 inhibits the growth of HeLa cells through AMPK and reverses epithelial-mesenchymal transition. Oncology Reports. 2017; 38: 237–244.

[11] Wei X, Xu L, Jeddo SF, Li K, Li X, Li J. MARK2 enhances cisplatin resistance via PI3K/AKT/NF-κB signaling pathway in osteosarcoma cells. American Journal of Translational Research. 2020; 12: 1807–1823.

[12] Ponnusamy L, Natarajan SR, Manoharan R. MARK2 potentiate aerobic glycolysis-mediated cell growth in breast cancer through regulating mTOR/HIF-1α and p53 pathways. Journal of Cellular Biochemistry. 2022; 123: 759–771.

[13] Natarajan SR, Ponnusamy L, Manoharan R. MARK2/4 promotes Warburg effect and cell growth in non-small cell lung carcinoma through the AMPKα1/mTOR/HIF-1α signaling pathway. BBA Molecular Cell Research. 2022; 1869: 119242.

[14] Koyanagi T, Suzuki Y, Saga Y, Machida S, Takei Y, Fujiwara H, et al. In vivo delivery of siRNA targeting vasohibin-2 decreases tumor angiogenesis and suppresses tumor growth in ovarian cancer. Cancer Science. 2013; 104: 1705–1710.

[15] Wassel M, Hamdy D, Elghazawy R. Evaluation of four vital pulp therapies for primary molars using a dual-cured tricalcium silicate (TheraCal PT): one-year results of a non-randomized clinical trial. Journal of Clinical Pediatric Dentistry. 2023; 47: 10–22.

[16] Matenia D, Hempp C, Timm T, Eikhof A, Mandelkow EM. Microtubule affinity-regulating kinase 2 (MARK2) turns on phosphatase and tensin homolog (PTEN)-induced kinase 1 (PINK1) at Thr-313, a mutation site in Parkinson disease: effects on mitochondrial transport. Journal of Biological Chemistry. 2012; 287: 8174–8186.

[17] Ghoneum A, Gonzalez D, Afify H, Shu J, Hegarty A, Adisa J, et al. Compound C inhibits ovarian cancer progression via PI3K-AKT-mTOR-NFκB pathway. Cancers. 2022; 14: 5099.

[18] Liu L, Huan L, Zhang Y, Wei W, Chen Z, Xu D, et al. Ubiquitin-specific protease 8 inhibits lipopolysaccharide-triggered pyroptosis of human bronchial epithelial cells by regulating PI3K/AKT and NF-κB pathways. Allergologia et Immunopathologia. 2022; 50: 96–103.

[19] Li C, Liu VW, Chan DW, Yao KM, Ngan HY. LY294002 and metformin cooperatively enhance the inhibition of growth and the induction of apoptosis of ovarian cancer cells. International Journal of Gynecologic Cancer. 2012; 22: 15–22.

[20] Wempe SL, Gamarra-Luques CD, Telleria CM. Synergistic lethality of mifepristone and LY294002 in ovarian cancer cells. Cancer Growth and Metastasis. 2013; 6: 1–13.

[21] Heinzl N, Koziel K, Maritschnegg E, Berger A, Pechriggl E, Fiegl H, et al. A comparison of four technologies for detecting p53 aggregates in ovarian cancer. Frontiers in Oncology. 2022; 12: 976725.