Luteoloside inhibiting the prostate cancer cells growth and promoting the tumor cells autophagy through AKT/mTOR pathway

Prostate cancer (PC) is one of the prevalent tumors in men causing higher mortality. Luteoloside has been discovered for suppressive role into the progression of some cancers. However, the Luteoloside’s regulatory functions regarding PC progression are not well understood. This study is thus designed to investigate the Luteoloside impact on PC progression. In this work, it was demonstrated that the PC cell proliferation was gradually inhibited with the increasing Luteoloside dose (0, 20, 40, 80 µM). Luteoloside also enhanced the PC cell apoptosis. It promoted the autophagy in PC through increasing microtubule-associated protein light chain (LC) 3II/LC3I levels and decreasing p62 levels. Moreover, the Luteoloside reduced phosphorylated-protein kinase B (p-AKT)/AKT and phosphorylated-mechanistic target of rapamycin (p-mTOR)/mTOR levels, indicating that it retarded the AKT/mTOR pathway. In conclusion, the Luteoloside inhibited PC cells growth and promoted tumor cells autophagy through AKT/mTOR pathway. This discovery suggested the Luteoloside as a potential drug in treating PC.

Luteoloside; Autophagy; Prostate cancer; AKT/mTOR pathway

[1] Nguyen-Nielsen M, Borre M. Diagnostic and therapeutic strategies for prostate cancer. Seminars in Nuclear Medicine. 2016; 46: 484–490.

[2] Murphy GP. Management of metastatic prostatic cancer. Progress in Clinical and Biological Research. 1988; 277: 127–134.

[3] Litwin MS, Tan H. The diagnosis and treatment of prostate cancer. JAMA. 2017; 317: 2532–2542.

[4] Kullmann T. Complementary elements to the pathogenesis, early detection and second line antihormonal therapy of prostate cancer. Journal of Men’s Health. 2022; 18: 155.

[5] Caporali S, De Stefano A, Calabrese C, Giovannelli A, Pieri M, Savini I, et al. Anti-inflammatory and active biological properties of the plant-derived bioactive compounds luteolin and luteolin 7-glucoside. Nutrients. 2022; 14: 1155.

[6] Shao J, Wang C, Li L, Liang H, Dai J, Ling X, et al. Luteoloside inhibits proliferation and promotes intrinsic and extrinsic pathway-mediated apoptosis involving MAPK and mTOR signaling pathways in human cervical cancer cells. International Journal of Molecular Sciences. 2018; 19: 1664.

[7] Ji J, Wang Z, Sun W, Li Z, Cai H, Zhao E, Cui H, et al. Effects of cynaroside on cell proliferation, apoptosis, migration and invasion though the MET/AKT/mTOR axis in gastric cancer. International Journal of Molecular Sciences. 2021; 22: 12125.

[8] Zhou M, Shen S, Zhao X, Gong X. Luteoloside induces G0/G1 arrest and pro-death autophagy through the ROS-mediated AKT/mTOR/p70S6K signalling pathway in human non-small cell lung cancer cell lines. Biochemical and Biophysical Research Communications. 2017; 494: 263–269.

[9] Fan SH, Wang YY, Lu J, Zheng YL, Wu DM, Li MQ, et al. Luteoloside suppresses proliferation and metastasis of hepatocellular carcinoma cells by inhibition of NLRP3 inflammasome. PLOS ONE. 2014; 9: e89961.

[10] Huang H, Wang Q, Du T, Lin C, Lai Y, Zhu D, et al. Matrine inhibits the progression of prostate cancer by promoting expression of GADD45B. The Prostate. 2018; 78: 327–335.

[11] Meng F, Yang J, Yang C, Jiang Y, Zhou Y, Yu B, et al. Vitexicarpin induces apoptosis in human prostate carcinoma PC-3 cells through G2/M phase arrest. Asian Pacific Journal of Cancer Prevention. 2012; 13: 6369–6374.

[12] Liang B, Cui S, Zou S. Leonurine suppresses prostate cancer growth in vitro and in vivo by regulating miR-18a-5p/SLC40a1 axis. Chinese Journal of Physiology. 2022; 65: 319–327.

[13] Tamgue O, Lei M. Triptolide promotes senescence of prostate cancer cells through histone methylation and heterochromatin formation. Asian Pacific Journal of Cancer Prevention. 2017; 18: 2519–2526.

[14] Ma X, Ren H, Zhang Y, Wang B, Ma H. LncRNA RHPN1-AS1 inhibition induces autophagy and apoptosis in prostate cancer cells via the miR-7-5p/EGFR/PI3K/AKT/mTOR signaling pathway. Environmental Toxicology. 2022; 37: 3013–3027.

[15] Cai F, Li J, Zhang J, Huang S. Knockdown of circ_CCNB2 sensitizes prostate cancer to radiation through repressing autophagy by the miR-30b-5p/KIF18a axis. Cancer Biotherapy and Radiopharmaceuticals. 2022; 37: 480–493.

[16] Nam RK, Benatar T, Amemiya Y, Sherman C, Seth A. Mir-139 regulates autophagy in prostate cancer cells through beclin-1 and mTOR signaling proteins. Anticancer Research. 2020; 40: 6649–6663.

[17] Yu Y, Song Y, Cheng L, Chen L, Liu B, Lu D, et al. CircCEMIP promotes anoikis-resistance by enhancing protective autophagy in prostate cancer cells. Journal of Experimental & Clinical Cancer Research. 2022; 41: 188.

[18] Ding M, Jiang C, Zhang Y, Zhao J, Han B, Xia S. SIRT7 depletion inhibits cell proliferation and androgen-induced autophagy by suppressing the AR signaling in prostate cancer. Journal of Experimental & Clinical Cancer Research. 2020; 39: 28.

[19] Cristofani R, Montagnani Marelli M, Cicardi ME, Fontana F, Marzagalli M, Limonta P, et al. Dual role of autophagy on docetaxel-sensitivity in prostate cancer cells. Cell Death & Disease. 2018; 9: 889.

[20] Lee EH, Lee JN, Park S, Chun SY, Yoon BH, Chung J, et al. Inhibition of TRPM7 suppresses migration and invasion of prostate cancer cells via inactivation of ERK1/2, Src and Akt pathway signaling. Journal of Men’s Health. 2022; 18: 144.

[21] Shorning BY, Dass MS, Smalley MJ, Pearson HB. The PI3K-AKT-mTOR pathway and prostate cancer: at the crossroads of AR, MAPK, and WNT signaling. International Journal of Molecular Sciences. 2020; 21: 4507.

[22] Qiu J, Zhang Y, Xie M. Chrysotoxine attenuates sevoflurane-induced neurotoxicity in vitro via regulating PI3K/AKT/GSK pathway. Signa Vitae. 2021; 17: 185–191.

[23] Peng Y, Wang Y, Zhou C, Mei W, Zeng C. PI3K/Akt/mTOR pathway and its role in cancer therapeutics: are we making headway? Frontiers in Oncology. 2022; 12: 819128.