Phenylethanol glycosides from Herba Cistanche improve the hypoxic tumor microenvironment and enhance the effects of oxaliplatin via the HIF‑1α signaling pathway

Wen,Limei; Hu,Junping; Zhang,Jiawei; Yang,Jianhua

doi:10.3892/mmr.2021.12156

Phenylethanol glycosides from Herba Cistanche improve the hypoxic tumor microenvironment and enhance the effects of oxaliplatin via the HIF‑1α signaling pathway

Authors:
- Limei Wen
- Junping Hu
- Jiawei Zhang
- Jianhua Yang
View Affiliations

Affiliations: College of Pharmacy, Xinjiang Medical University, Urumqi, Xinjiang 830054, P.R. China
Published online on: May 17, 2021 https://doi.org/10.3892/mmr.2021.12156
Article Number: 517
Copyright: © Wen et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Liver cancer is one of the most common types of malignant tumor, and is characterized by high malignancy, rapid progression, high morbidity and mortality. Oxaliplatin (OXA) has been reported to have marked efficiency against advanced liver cancer with tolerable toxicity. In solid tumors, the hypoxic microenvironment promotes epithelial‑mesenchymal transition (EMT), which can also induce drug resistance of liver cancer to platinum drugs. Herba Cistanche (Cistanche tubulosa) has been frequently used in traditional Chinese medicine and the phenylethanol glycosides from Herba Cistanche (CPhGs) are the major active components. The present study aimed to investigate the effects of CPhGs on viability, apoptosis, migration and invasion of liver cancer cells. HepG2 liver cancer cells were divided into the control, DMSO, CoCl₂, OXA, OXA + CoCl₂ and CPhGs + OXA + CoCl₂ groups. Subsequently, reverse transcription‑quantitative PCR and western blot analysis were performed to determine the expression levels of hypoxia‑inducible factor 1α (HIF‑1α), lysyl oxidase‑like 2 (LOXL2) and EMT‑related genes and proteins (i.e., E‑cadherin and Twist), in order to investigate the effects of CPhGs on liver cancer. The results demonstrated that CPhGs could enhance the effects of OXA on liver cancer, and inhibit the migration, invasion and apoptotic rate of liver cancer cells. Additionally, CPhGs treatment effectively induced downregulation of HIF‑1α, LOXL2 and Twist, and upregulation of E‑cadherin. The present findings indicated that CPhGs triggered a significant increase in sensitivity to OXA and suppression of hypoxia‑induced EMT in liver cancer by inhibiting the HIF‑1α signaling pathway. Therefore, CPhGs may be considered an effective platinum drug sensitizer, which could improve chemotherapeutic efficacy in patients with liver cancer.

View Figures

View References

1	Hepatocellular carcinoma. Nat Rev Dis Primers. 2:160192016. View Article : Google Scholar : PubMed/NCBI
2	Gingold JA, Zhu D, Lee DF, Kaseb A and Chen J: Genomic profiling and metabolic homeostasis in primary liver cancers. Trends Mol Med. 24:395–411. 2018. View Article : Google Scholar : PubMed/NCBI
3	McGuire S: World cancer report 2014. Geneva, Switzerland: World health organization, international agency for research on cancer, WHO press, 2015. Adv Nutr. 7:418–419. 2016. View Article : Google Scholar : PubMed/NCBI
4	Gholamreza K, Jadidi-Niaragh F, Jahromi AS, Zandi K and Hojjat-Farsangi M: Mechanisms of tumor cell resistance to the current targeted-therapy agents. Tumour Biol. 37:10021–10039. 2016. View Article : Google Scholar : PubMed/NCBI
5	Dong X and Mumper RJ: Nanomedicinal strategies to treat multidrug-resistant tumors: Current progress. Nanomedicine (Lond). 5:597–615. 2010. View Article : Google Scholar : PubMed/NCBI
6	Xie Y and Zhong DW: AEG-1 is associated with hypoxia-induced hepatocellular carcinoma chemoresistance via regulating PI3K/AKT/HIF-1alpha/MDR-1 pathway. EXCLI J. 15:745–757. 2016.PubMed/NCBI
7	Xiong H, Ni Z, He J, Jiang S, Li X, He J, Gong W, Zheng L, Chen S, Li B, et al: LncRNA HULC triggers autophagy via stabilizing Sirt1 and attenuates the chemosensitivity of HCC cells. Oncogene. 36:3528–3540. 2017. View Article : Google Scholar : PubMed/NCBI
8	Gade TPF, Tucker E, Nakazawa MS, Hunt SJ, Wong W, Krock B, Weber CN, Nadolski GJ, Clark TWI, Soulen MC, et al: Ischemia induces quiescence and autophagy dependence in hepatocellular carcinoma. Radiology. 283:702–710. 2017. View Article : Google Scholar : PubMed/NCBI
9	Siegel RL, Miller KD and Jemal A: Cancer statistics, 2017. CA Cancer J Clin. 67:7–30. 2017. View Article : Google Scholar : PubMed/NCBI
10	Dong LQ, Shen BQ and Ma Y: Research progress of hypoxia microenvironment in hepatocellular carcinoma. Zhong Guo Pu Wai Ji Chu Yu Lin Chuang Za Zhi. 25:1254–1258. 2018.(In Chinese).
11	Moon HJ, Finney J, Ronnebaum T and Mure M: Human lysyl oxidase-like 2. Bioorg Chem. 57:231–241. 2014. View Article : Google Scholar : PubMed/NCBI
12	Ferreira S, Saraiva N, Rijo P and Fernandes AS: LOXL2 inhibitors and breast cancer progression. Antioxidants (Basel). 10:3122021. View Article : Google Scholar : PubMed/NCBI
13	Philp CJ, Siebeke I, Clements D, Miller S, Habgood A, John AE, Navaratnam V, Hubbard RB, Jenkins G and Johnson SR: Extracellular matrix cross-linking enhances fibroblast growth and protects against matrix proteolysis in lung fibrosis. Am J Respir Cell Mol Biol. 58:594–603. 2018. View Article : Google Scholar : PubMed/NCBI
14	Galván JA, Zlobec I, Wartenberg M, Lugli A, Gloor B, Perren A and Karamitopoulou E: Expression of E-cadherin repressors SNAIL, ZEB1 and ZEB2 by tumour and stromal cells influences tumour-budding phenotype and suggests heterogeneity of stromal cells in pancreatic cancer. Br J Cancer. 112:1944–1950. 2015. View Article : Google Scholar
15	Gu C, Yang X and Huang L: Cistanches herba: A neuropharmacology review. Front Pharmacol. 7:2892016. View Article : Google Scholar : PubMed/NCBI
16	Fu Z, Fan X, Wang X and Gao X: Cistanches Herba: An overview of its chemistry, pharmacology, and pharmacokinetics property. J Ethnopharmacol. 219:233–247. 2018. View Article : Google Scholar : PubMed/NCBI
17	Hu Q, You SP, Liu T, Wang B, Liu X and Jiang Y: An investigation on the anti-liver cancer effect of cistanche. Carcinog Teratog Mutagen. 30:194–199. 2018.
18	Mao J, Tian Y, Wang C, Jiang K, Li R, Yao Y, Zhang R, Sun D, Liang R, Gao Z, et al: CBX2 regulates proliferation and apoptosis via the phosphorylation of YAP in hepatocellular carcinoma. J Cancer. 10:2706–2719. 2019. View Article : Google Scholar : PubMed/NCBI
19	Qin Y, Liu HJ, Li M, Zhai DH, Tang YH, Yang L, Qiao KL, Yang JH, Zhong WL, Zhang Q, et al: Salidroside improves the hypoxic tumor microenvironment and reverses the drug resistance of platinum drugs via HIF-1α signaling pathway. EBioMedicine. 38:25–36. 2018. View Article : Google Scholar : PubMed/NCBI
20	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
21	Vaupel P: Tumor microenvironmental physiology and its implications for radiation oncology. Semin Radiat Oncol. 14:198–206. 2004. View Article : Google Scholar : PubMed/NCBI
22	Chen C and Lou T: Hypoxia inducible factors in hepatocellular carcinoma. Oncotarget. 8:46691–46703. 2017. View Article : Google Scholar : PubMed/NCBI
23	Schwabe RF and Luedde T: Apoptosis and necroptosis in the liver: A matter of life and death. Nat Rev Gastroenterol Hepatol. 15:738–752. 2018. View Article : Google Scholar : PubMed/NCBI
24	Kanda T, Matsuoka S, Yamazaki M, Shibata T, Nirei K, Takahashi H, Kaneko T, Fujisawa M, Higuchi T, Nakamura H, et al: Apoptosis and non-alcoholic fatty liver diseases. World J Gastroenterol. 24:2661–2672. 2018. View Article : Google Scholar : PubMed/NCBI
25	Pittala S, Krelin Y and Shoshan-Barmatz V: Targeting liver cancer and associated pathologies in mice with a mitochondrial VDAC1-based Peptide. Neoplasia. 20:594–609. 2018. View Article : Google Scholar : PubMed/NCBI
26	Jing ZT, Liu W, Xue CR, Wu SX, Chen WN, Lin XJ and Lin X: AKT activator SC79 protects hepatocytes from TNF-α-mediated apoptosis and alleviates d-Gal/LPS-induced liver injury. Am J Physiol Gastrointest Liver Physiol. 316:G387–G396. 2019. View Article : Google Scholar : PubMed/NCBI
27	Zhu YJ, Zheng B, Wang HY and Chen L: New knowledge of the mechanisms of sorafenib resistance in liver cancer. Acta Pharmacol Sin. 38:614–622. 2017. View Article : Google Scholar : PubMed/NCBI
28	Wei R, Cao J and Yao S: Matrine promotes liver cancer cell apoptosis by inhibiting mitophagy and PINK1/Parkin pathways. Cell Stress Chaperones. 23:1295–1309. 2018. View Article : Google Scholar : PubMed/NCBI
29	Shen L and Zhang G, Lou Z, Xu G and Zhang G: Cryptotanshinone enhances the effect of arsenic trioxide in treating liver cancer cell by inducing apoptosis through downregulating phosphorylated-STAT3 in vitro and in vivo. BMC Complement Altern Med. 17:1062017. View Article : Google Scholar : PubMed/NCBI
30	Wu F, Zhang J, Liu Y, Zheng Y and Hu N: HIF1α genetic variants and protein expressions determine the response to platinum based chemotherapy and clinical outcome in patients with advanced NSCLC. Cell Physiol Biochem. 32:1566–1576. 2013. View Article : Google Scholar : PubMed/NCBI
31	Heerboth S, Housman G, Leary M, Longacre M, Byler S, Lapinska K, Willbanks A and Sarkar S: EMT and tumor metastasis. Clin Transl Med. 4:62015. View Article : Google Scholar : PubMed/NCBI
32	Hapke RY and Haake SM: Hypoxia-induced epithelial to mesenchymal transition in cancer. Cancer Lett. 487:10–20. 2020. View Article : Google Scholar : PubMed/NCBI
33	Zhao Z, Rahman MA, Chen ZG and Shin DM: Multiple biological functions of Twist1 in various cancers. Oncotarget. 8:20380–20393. 2017. View Article : Google Scholar : PubMed/NCBI
34	Goossens S, Vandamme N, Van Vlierberghe P and Berx G: EMT transcription factors in cancer development re-evaluated: Beyond EMT and MET. Biochim Biophys Acta Rev Cancer. 1868:584–591. 2017. View Article : Google Scholar : PubMed/NCBI
35	Shao B, Zhao X, Liu T, Zhang Y, Sun R, Dong X, Liu F, Zhao N, Zhang D, Wu L, et al: LOXL2 promotes vasculogenic mimicry and tumour aggressiveness in hepatocellular carcinoma. J Cell Mol Med. 23:1363–1374. 2019. View Article : Google Scholar : PubMed/NCBI
36	Wu L, Zhang Y, Zhu Y, Cong Q, Xiang Y and Fu L: The effect of LOXL2 in hepatocellular carcinoma. Mol Med Rep. 14:1923–1932. 2016. View Article : Google Scholar : PubMed/NCBI
37	Peng L, Ran YL, Hu H, Yu L, Liu Q, Zhou Z, Sun YM, Sun LC, Pan J, Sun LX, et al: Secreted LOXL2 is a novel therapeutic target that promotes gastric cancer metastasis via the Src/FAK pathway. Carcinogenesis. 30:1660–1669. 2009. View Article : Google Scholar : PubMed/NCBI