Login Register Cart 0
Generic placeholder image

Current Cancer Drug Targets

Editor-in-Chief

ISSN (Print): 1568-0096
ISSN (Online): 1873-5576

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

Withaferin A Inhibits Liver Cancer Tumorigenesis by Suppressing Aerobic Glycolysis through the p53/IDH1/HIF-1α Signaling Axis

Author(s): Xiangyang Zhou, Di Wu, Linmiao Zhu, Ruohan Li, Haitao Yu* and Wenjuan Li*

Volume 24, Issue 5, 2024

Published on: 21 November, 2023

Page: [534 - 545] Pages: 12

DOI: 10.2174/0115680096262915231026050602

Abstract

Background: The energy supply of certain cancer cells depends on aerobic glycolysis rather than oxidative phosphorylation. Our previous studies have shown that withaferin A (WA), a lactone compound derived from Withania somnifera, suppresses skin carcinogenesis at least partially by stabilizing IDH1 and promoting oxidative phosphorylation. Here, we have extended our studies to evaluate the anti-tumor effect of WA in liver cancer.

Methods: Differential expression of glycolysis-related genes between liver cancer tissues and normal tissues and prognosis were verified using an online database. Glycolysis-related protein expression was detected using western blot after overexpression and knockdown of IDH1 and mitochondrial membrane potential assay based on JC-1, and mitochondrial complex I activity was also detected. The inhibitory effect of WA on the biological functions of HepG2 cells was detected along with cell viability using MTT assay, scratch assay, clone formation assay, glucose consumption and lactate production assay. Western blot and qRT-PCR were used to detect the expression of proteins and genes related to IDH1, p53 and HIF1α signaling pathways.

Results: We first identified that IDH1 expression was downregulated in human liver cancer cells compared to normal liver cells. Next, we found that treatment of HepG2 cells with WA resulted in significantly increased protein levels of IDH1, accompanied by decreased levels of several glycolytic enzymes. Furthermore, we found that WA stabilized IDH1 proteins by inhibiting the degradation by the proteasome. The tumor suppressor p53 was also upregulated by WA treatment, which played a critical role in the upregulation of IDH1 and downregulation of the glycolysis-related genes. Under hypoxic conditions, glycolysis-related genes were induced, which was suppressed by WA treatment, and IDH1 expression was still maintained at higher levels under hypoxia.

Conclusion: Taken together, our results indicated that WA suppresses liver cancer tumorigenesis by p53-mediated IDH1 upregulation, which promotes mitochondrial respiration, thereby inhibiting the HIF-1α pathway and blocking aerobic glycolysis.

« Previous Next »
Graphical Abstract

[1]
Chakraborty, S.; Mallick, D.; Goswami, M.; Guengerich, F.P.; Chakrabarty, A.; Chowdhury, G. The natural products withaferin a and withanone from the medicinal herb Withania somnifera are covalent inhibitors of the SARS-CoV-2 main protease. J. Nat. Prod., 2022, 85(10), 2340-2350.
[http://dx.doi.org/10.1021/acs.jnatprod.2c00521] [PMID: 36098617]
[2]
Lee, J.; Liu, J.; Feng, X.; Salazar Hernández, M.A.; Mucka, P.; Ibi, D.; Choi, J.W.; Ozcan, U. Withaferin A is a leptin sensitizer with strong antidiabetic properties in mice. Nat. Med., 2016, 22(9), 1023-1032.
[http://dx.doi.org/10.1038/nm.4145] [PMID: 27479085]
[3]
Hassannia, B.; Wiernicki, B.; Ingold, I.; Qu, F.; Van Herck, S.; Tyurina, Y.Y.; Bayır, H.; Abhari, B.A.; Angeli, J.P.F.; Choi, S.M.; Meul, E.; Heyninck, K.; Declerck, K.; Chirumamilla, C.S.; Lahtela-Kakkonen, M.; Van Camp, G.; Krysko, D.V.; Ekert, P.G.; Fulda, S.; De Geest, B.G.; Conrad, M.; Kagan, V.E.; Vanden Berghe, W.; Vandenabeele, P.; Vanden Berghe, T. Nano-targeted induction of dual ferroptotic mechanisms eradicates high-risk neuroblastoma. J. Clin. Invest., 2018, 128(8), 3341-3355.
[http://dx.doi.org/10.1172/JCI99032] [PMID: 29939160]
[4]
Hassannia, B.; Logie, E.; Vandenabeele, P.; Vanden Berghe, T.; Vanden Berghe, W.; Withaferin, A. Withaferin A: From ayurvedic folk medicine to preclinical anti-cancer drug. Biochem. Pharmacol., 2020, 173, 113602.
[http://dx.doi.org/10.1016/j.bcp.2019.08.004] [PMID: 31404528]
[5]
Kumar, S.; Mathew, S.O.; Aharwal, R.P.; Tulli, H.S.; Mohan, C.D.; Sethi, G.; Ahn, K-S.; Webber, K.; Sandhu, S.S.; Bishayee, A. Withaferin A: A pleiotropic anticancer agent from the indian medicinal plant withania somnifera (L.) Dunal. Pharmaceuticals, 2023, 16(2), 160.
[6]
Xu, K.; Zhang, C.; Li, Y.; Xi, X.; Zheng, L.; Meng, M.; Liu, T.; Zhao, Y.; Li, W. Withaferin A suppresses skin tumor promotion by inhibiting proteasome-dependent isocitrate dehydrogenase 1 degradation. Transl. Cancer Res., 2019, 8(6), 2449-2460.
[http://dx.doi.org/10.21037/tcr.2019.09.57] [PMID: 35116997]
[7]
Hirschey, M.D.; DeBerardinis, R.J.; Diehl, A.M.E.; Drew, J.E.; Frezza, C.; Green, M.F.; Jones, L.W.; Ko, Y.H.; Le, A.; Lea, M.A.; Locasale, J.W.; Longo, V.D.; Lyssiotis, C.A.; McDonnell, E.; Mehrmohamadi, M.; Michelotti, G.; Muralidhar, V.; Murphy, M.P.; Pedersen, P.L.; Poore, B.; Raffaghello, L.; Rathmell, J.C.; Sivanand, S.; Vander Heiden, M.G.; Wellen, K.E. Dysregulated metabolism contributes to oncogenesis. Semin. Cancer Biol., 2015, 35, S129-S150.
[http://dx.doi.org/10.1016/j.semcancer.2015.10.002] [PMID: 26454069]
[8]
Wu, J.; Hu, L.; Chen, M.; Cao, W.; Chen, H.; He, T. Pyruvate kinase M2 overexpression and poor prognosis in solid tumors of digestive system: evidence from 16 cohort studies. OncoTargets Ther., 2016, 9, 4277-4288.
[http://dx.doi.org/10.2147/OTT.S106508] [PMID: 27478385]
[9]
Warburg, O. On the origin of cancer cells. Science, 1956, 123(3191), 309-314.
[http://dx.doi.org/10.1126/science.123.3191.309] [PMID: 13298683]
[10]
Macheda, M.L.; Rogers, S.; Best, J.D. Molecular and cellular regulation of glucose transporter (GLUT) proteins in cancer. J. Cell. Physiol., 2005, 202(3), 654-662.
[http://dx.doi.org/10.1002/jcp.20166] [PMID: 15389572]
[11]
Allison, S.J.; Knight, J.R.P.; Granchi, C.; Rani, R.; Minutolo, F.; Milner, J.; Phillips, R.M. Identification of LDH-A as a therapeutic target for cancer cell killing via (i) p53/NAD(H)-dependent and (ii) p53-independent pathways. Oncogenesis, 2014, 3(5), e102.
[http://dx.doi.org/10.1038/oncsis.2014.16] [PMID: 24819061]
[12]
Satriano, L.; Lewinska, M.; Rodrigues, P.M.; Banales, J.M.; Andersen, J.B. Metabolic rearrangements in primary liver cancers: Cause and consequences. Nat. Rev. Gastroenterol. Hepatol., 2019, 16(12), 748-766.
[http://dx.doi.org/10.1038/s41575-019-0217-8] [PMID: 31666728]
[13]
Yao, F.; Zhao, T.; Zhong, C.; Zhu, J.; Zhao, H. LDHA is necessary for the tumorigenicity of esophageal squamous cell carcinoma. Tumour Biol., 2013, 34(1), 25-31.
[http://dx.doi.org/10.1007/s13277-012-0506-0] [PMID: 22961700]
[14]
Dong, G.; Mao, Q.; Xia, W.; Xu, Y.; Wang, J.; Xu, L.; Jiang, F. PKM2 and cancer: The function of PKM2 beyond glycolysis. Oncol. Lett., 2016, 11(3), 1980-1986.
[http://dx.doi.org/10.3892/ol.2016.4168] [PMID: 26998110]
[15]
Gabriely, G.; Wheeler, M.A.; Takenaka, M.C.; Quintana, F.J. Role of AHR and HIF-1α in glioblastoma metabolism. Trends Endocrinol. Metab., 2017, 28(6), 428-436.
[http://dx.doi.org/10.1016/j.tem.2017.02.009] [PMID: 28318896]
[16]
Xue, Y.N.; Yu, B.B.; Li, J.L.; Guo, R.; Zhang, L.C.; Sun, L.K.; Liu, Y.N.; Li, Y. Zinc and p53 disrupt mitochondrial binding of HK2 by phosphorylating VDAC1. Exp. Cell Res., 2019, 374(1), 249-258.
[http://dx.doi.org/10.1016/j.yexcr.2018.12.002] [PMID: 30528266]
[17]
Qi, Y.; Zhang, C.; Wu, D.; Zhang, Y.; Zhao, Y.; Li, W. Indole-3-carbinol stabilizes p53 to induce miR-34a, which targets LDHA to block aerobic glycolysis in liver cancer cells. Pharmaceuticals, 2022, 15(10), 1257.
[http://dx.doi.org/10.3390/ph15101257] [PMID: 36297369]
[18]
Romanidou, O.; Kotoula, V.; Fountzilas, G. Bridging cancer biology with the clinic: Comprehending and exploiting IDH gene mutations in gliomas. Cancer Genomics Proteomics, 2018, 15(5), 421-436.
[http://dx.doi.org/10.21873/cgp.20101] [PMID: 30194083]
[19]
Cardaci, S.; Ciriolo, M.R. TCA cycle defects and cancer: When metabolism tunes redox state. Int. J. Cell Biol., 2012, 2012, 1-9.
[http://dx.doi.org/10.1155/2012/161837] [PMID: 22888353]
[20]
Laba, P.; Wang, J.; Zhang, J. Low level of isocitrate dehydrogenase 1 predicts unfavorable postoperative outcomes in patients with clear cell renal cell carcinoma. BMC Cancer, 2018, 18(1), 852.
[http://dx.doi.org/10.1186/s12885-018-4747-1] [PMID: 30153799]
[21]
Ogura, R.; Tsukamoto, Y.; Natsumeda, M.; Isogawa, M.; Aoki, H.; Kobayashi, T.; Yoshida, S.; Okamoto, K.; Takahashi, H.; Fujii, Y.; Kakita, A. Immunohistochemical profiles of I DH 1, MGMT and P 53: Practical significance for prognostication of patients with diffuse gliomas. Neuropathology, 2015, 35(4), 324-335.
[http://dx.doi.org/10.1111/neup.12196] [PMID: 25950388]
[22]
Fu, J.; Wang, H. Precision diagnosis and treatment of liver cancer in China. Cancer Lett., 2018, 412, 283-288.
[http://dx.doi.org/10.1016/j.canlet.2017.10.008] [PMID: 29050983]
[23]
Faubert, B.; Solmonson, A.; DeBerardinis, R.J. Metabolic reprogramming and cancer progression. Science, 2020, 368(6487), eaaw5473.
[http://dx.doi.org/10.1126/science.aaw5473] [PMID: 32273439]
[24]
Marín-Hernández, A.; Gallardo-Pérez, J.; Ralph, S.; Rodríguez-Enríquez, S.; Moreno-Sánchez, R. HIF-1alpha modulates energy metabolism in cancer cells by inducing over-expression of specific glycolytic isoforms. Mini Rev. Med. Chem., 2009, 9(9), 1084-1101.
[http://dx.doi.org/10.2174/138955709788922610] [PMID: 19689405]
[25]
Valcarcel-Jimenez, L.; Gaude, E.; Torrano, V.; Frezza, C.; Carracedo, A. Mitochondrial Metabolism: Yin and Yang for Tumor Progression. Trends Endocrinol. Metab., 2017, 28(10), 748-757.
[http://dx.doi.org/10.1016/j.tem.2017.06.004] [PMID: 28938972]
[26]
Unruh, D.; Schwarze, S.R.; Khoury, L.; Thomas, C.; Wu, M.; Chen, L.; Chen, R.; Liu, Y.; Schwartz, M.A.; Amidei, C.; Kumthekar, P.; Benjamin, C.G.; Song, K.; Dawson, C.; Rispoli, J.M.; Fatterpekar, G.; Golfinos, J.G.; Kondziolka, D.; Karajannis, M.; Pacione, D.; Zagzag, D.; McIntyre, T.; Snuderl, M.; Horbinski, C. Mutant IDH1 and thrombosis in gliomas. Acta Neuropathol., 2016, 132(6), 917-930.
[http://dx.doi.org/10.1007/s00401-016-1620-7] [PMID: 27664011]
[27]
Dom, M.; Vanden Berghe, W.; Van Ostade, X. Broad-spectrum antitumor properties of Withaferin A: A proteomic perspective. RSC Med. Chem, 2020, 11(1), 30-50.
[http://dx.doi.org/10.1039/C9MD00296K] [PMID: 33479603]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy