Pachymic acid exerts antitumor activities by modulating the Wnt/β-catenin signaling pathway via targeting PTP1B

Abstract

Objective: To determine the inhibitory effects of pachymic acid on lung adenocarcinoma (LUAD) cells and elucidate its underlying mechanism. Methods: CCK-8, wound healing, Transwell, Western blot, tube formation, and immunofluorescence assays were carried out to measure the effects of various concentrations of pachymic acid on LUAD cell proliferation, metastasis, angiogenesis as well as autophagy. Subsequently, molecular docking technology was used to detect the potential targeted binding association between pachymic acid and protein tyrosine phosphatase 1B (PTP1B). Moreover, PTP1B was overexpressed in A549 cells to detect the specific mechanisms of pachymic acid. Results: Pachymic acid suppressed LUAD cell viability, metastasis as well as angiogenesis while inducing cell autophagy. It also targeted PTP1B and lowered PTP1B expression. However, PTP1B overexpression reversed the effects of pachymic acid on metastasis, angiogenesis, and autophagy as well as the expression of Wnt3a and β-catenin in LUAD cells. Conclusions: Pachymic acid inhibits metastasis and angiogenesis, and promotes autophagy in LUAD cells by modulating the Wnt/β-catenin signaling pathway via targeting PTP1B.

Keywords

Pachymic acid / Lung adenocarcinoma / Protein tyrosine phosphatase 1B / Wnt/β-catenin signaling pathway / Metastasis / Angiogenesis / Autophagy

Conflict of interest statement

The authors have no conflict of interest to declare.

Funding

The study was supported by the Zhejiang Province Traditional Chinese Medicine Health Science and Technology Program (2023ZL570).

Data availability statement

The data supporting the findings of this study are available from the corresponding authors upon request.

Authors’ contributions

FZ designed the experiment. HZ and KZ operated the experiment and wrote the article. XFZ, YHD, BZ, WM, and QSD processed the experimental data and ensured the authenticity and accuracy of the experimental data. All the authors agreed to the publication of the article.

References

[1] Bernhardt EB, Jalal SI. Small cell lung cancer. Cancer Treat Res 2016; 170: 301-322.

[2] Torre LA, Siegel RL, Jemal A. Lung cancer statistics. Adv Exp Med Biol 2016; 893: 1-19.

[3] Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics, 2021. CA Cancer J Clin 2021; 71(1): 7-33.

[4] Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin 2018; 68(1): 7-30.

[5] Xiang Y, Guo Z, Zhu P, Chen J, Huang Y. Traditional Chinese medicine as a cancer treatment: Modern perspectives of ancient but advanced science. Cancer Med 2019; 8(5): 1958-1975.

[6] Li Z, Feiyue Z, Gaofeng L. Traditional Chinese medicine and lung cancer-From theory to practice. Biomed Pharmacother 2021; 137: 111381.

[7] Jiang GP, Liao YJ, Huang LL, Zeng XJ, Liao XH. Effects and molecular mechanism of pachymic acid on ferroptosis in renal ischemia reperfusion injury. Mol Med Rep 2021; 23(1). doi: 10.3892/mmr.2020.11704.

[8] Li F, Chen M, Ji J, Tang R, Huang J, Zhang X, et al. Pachymic acid alleviates experimental pancreatic fibrosis through repressing NLRP3 inflammasome activation. Biosci Biotechnol Biochem 2022; 86(11): 1497-1505.

[9] Ma J, Liu J, Lu C, Cai D. Pachymic acid induces apoptosis via activating ROS-dependent JNK and ER stress pathways in lung cancer cells. Cancer Cell Int 2015; 15: 78.

[10] Li JM, Li YC, Kong LD, Hu QH. Curcumin inhibits hepatic protein-tyrosine phosphatase 1B and prevents hypertriglyceridemia and hepatic steatosis in fructose-fed rats. Hepatology 2010; 51(5): 1555-1566.

[11] Liu H, Wu Y, Zhu S, Liang W, Wang Z, Wang Y, et al. PTP1B promotes cell proliferation and metastasis through activating src and ERK1/2 in non-small cell lung cancer. Cancer Lett 2015; 359(2): 218-225.

[12] Barahona I, Rada P, Calero-Perez S, Grillo-Risco R, Pereira L, Soler-Vazquez MC, et al. Ptpn1 deletion protects oval cells against lipoapoptosis by favoring lipid droplet formation and dynamics. Cell Death Differ 2022; 29(12): 2362-2380.

[13] Wang Y, Yan F, Zhang W, Pang S, Jiang F. Inhibiting protein tyrosine phosphatase 1B to improve regenerative functions of endothelial cells. J Cardiovasc Pharmacol 2018; 71(2): 59-64.

[14] Zheng LY, Zhou DX, Lu J, Zhang WJ, Zou DJ. Down-regulated expression of the protein-tyrosine phosphatase 1B (PTP1B) is associated with aggressive clinicopathologic features and poor prognosis in hepatocellular carcinoma. Biochem Biophys Res Commun 2012; 420(3): 680-684.

[15] Younis NN, Mohamed HE, Shaheen MA, Abdelghafour AM, Hammad SK. Potential therapeutic efficacy of pachymic acid in chronic kidney disease induced in rats: Role of Wnt/beta-catenin/renin-angiotensin axis. J Pharm Pharmacol 2022; 74(1): 112-123.

[16] Zhang HJ, Chang WJ, Jia CY, Qiao L, Zhou J, Chen Q, et al. Destrin contributes to lung adenocarcinoma progression by activating Wnt/β-catenin signaling pathway. Mol Cancer Res 2020; 18(12): 1789-1802.

[17] Wang Z, Fang Z, Chen G, Liu B, Xu J, Li F, et al. Chromobox 4 facilitates tumorigenesis of lung adenocarcinoma through the Wnt/β-catenin pathway. Neoplasia 2021; 23(2): 222-233.

[18] Ling H, Jia X, Zhang Y, Gapter LA, Lim YS, Agarwal R, et al. Pachymic acid inhibits cell growth and modulates arachidonic acid metabolism in nonsmall cell lung cancer A549 cells. Mol Carcinog 2010; 49(3): 271-282.

[19] Leelawat S, Leelawat K, Wannakup T, Saingam W, Khamthong N, Madaka F, et al. Anticancer activity of Δ9-tetrahydrocannabinol and cannabinol in vitro and in human lung cancer xenograft. Asian Pac J Trop Biomed 2022; 12(8): 323-332.

[20] Spella M, Stathopoulos GT. Immune resistance in lung adenocarcinoma. Cancers (Basel) 2021; 13(3). doi: 10.3390/cancers13030384.

[21] Su L, Zhao J, Su H, Wang Y, Huang W, Jiang X, et al. CircRNAs in lung adenocarcinoma: Diagnosis and therapy. Curr Gene Ther 2022; 22(1): 15-22.

[22] Xiang M, Li R, Zhang Z, Song X. Advances in the research of the regulation of Chinese traditional medicine monomer and its derivatives on autophagy in non-small cell lung cancer. Zhongguo Fei Ai Za Zhi 2017; 20(3): 205-212.

[23] Wang H, Luo Y, Chu Z, Ni T, Ou S, Dai X, et al. Poria acid, triterpenoids extracted from Poria cocos, inhibits the invasion and metastasis of gastric cancer cells. Molecules 2022; 27(11). doi: 10.3390/molecules27113629.

[24] Ma J, Liu J, Lu CW, Cai DF. Pachymic acid modified carbon nanoparticles reduced angiogenesis via inhibition of MMP-3. Int J Clin Exp Pathol 2015; 8(5): 5464-5470.

[25] Levine B, Kroemer G. Biological functions of autophagy genes: A disease perspective. Cell 2019; 176(1-2): 11-42.

[26] Yu Z, Tang H, Chen S, Xie Y, Shi L, Xia S, et al. Exosomal LOC85009 inhibits docetaxel resistance in lung adenocarcinoma through regulating ATG5-induced autophagy. Drug Resist Updat 2023; 67. doi: 10.1016/j.drup.2022.100915.

[27] Lv D, Luo X, Chen Z, Liu J, Liu M, Li Y, et al. Apelin/APJ signaling activates autophagy to promote human lung adenocarcinoma cell migration. Life Sci 2021; 281. doi: 10.1016/j.lfs.2021.119763.

[28] Lee SG, Kim MM. Pachymic acid promotes induction of autophagy related to IGF-1 signaling pathway in WI-38 cells. Phytomedicine 2017; 36: 82-87.

[29] Wiede F, Lu KH, Du X, Zeissig MN, Xu R, Goh PK, et al. PTP1B is an intracellular checkpoint that limits T-cell and CAR T-cell antitumor immunity. Cancer Discov 2022; 12(3): 752-773.

[30] Yuan F, Gao Q, Tang H, Shi J, Zhou Y. Ophiopogonin-B targets PTP1B to inhibit the malignant progression of hepatocellular carcinoma by regulating the PI3K/AKT and AMPK signaling pathways. Mol Med Rep 2022; 25(4). doi: 10.3892/mmr.2022.12638.

[31] Gogiraju R, Bochenek ML, Schafer K. Angiogenic endothelial cell signaling in cardiac hypertrophy and heart failure. Front Cardiovasc Med 2019; 6. doi: 10.3389/fcvm.2019.00020.

[32] Ito Y, Hsu MF, Bettaieb A, Koike S, Mello A, Calvo-Rubio M, et al. Protein tyrosine phosphatase 1B deficiency in podocytes mitigates hyperglycemia-induced renal injury. Metabolism 2017; 76: 56-69.

[33] Kandadi MR, Panzhinskiy E, Roe ND, Nair S, Hu D, Sun A. Deletion of protein tyrosine phosphatase 1B rescues against myocardial anomalies in high fat diet-induced obesity: Role of AMPK-dependent autophagy. Biochim Biophys Acta 2015; 1852(2): 299-309.

[34] Pan J, Fang S, Tian H, Zhou C, Zhao X, Tian H, et al. lncRNA JPX/miR-33a-5p/Twist1 axis regulates tumorigenesis and metastasis of lung cancer by activating Wnt/β-catenin signaling. Mol Cancer 2020; 19(1): 9.

[35] Zhong C, Chen M, Chen Y, Yao F, Fang W. Loss of DSTYK activates Wnt/β-catenin signaling and glycolysis in lung adenocarcinoma. Cell Death Dis 2021; 12(12): 1122.

[36] Wu XT, Wang YH, Cai XY, Dong Y, Cui Q, Zhou YN, et al. RNF115 promotes lung adenocarcinoma through Wnt/β-catenin pathway activation by mediating APC ubiquitination. Cancer Metab 2021; 9(1): 7.

[37] Xu J, Lv W, Hu Y, Wang L, Wang Y, Cao J, et al. Wnt3a Expression is associated with epithelial-mesenchymal transition and impacts prognosis of lung adenocarcinoma patients. J Cancer 2017; 8(13): 2523-2531.

[38] Luo J, Yao Y, Ji S, Sun Q, Xu Y, Liu K, et al. PITX2 enhances progression of lung adenocarcinoma by transcriptionally regulating WNT3A and activating Wnt/β-catenin signaling pathway. Cancer Cell Int 2019; 19: 96.

[39] Wang S, Qiu M, Xia W, Xu Y, Mao Q, Wang J, et al. Glypican-5 suppresses pithelial-mesenchymal transition of the lung adenocarcinoma by competitively binding to Wnt3a. Oncotarget 2016; 7(48): 79736-79746.