Hinokitiol reduces tumor metastasis by inhibiting heparanase via extracellular signal-regulated kinase and protein kinase B pathway

Abstract

Heparanase cleaves the extracellular matrix by degrading heparan sulfate that ultimately leads to cell invasion and metastasis; a condition that causes high mortality among cancer patients. Many of the anticancer drugs available today are natural products of plant origin, such as hinokitiol. In the previous report, it was revealed that hinokitiol plays an essential role in anti-inflammatory and anti-oxidation processes and promote apoptosis or autophagy resulting to the inhibition of tumor growth and differentiation. Therefore, this study explored the effects of hinokitiol on the cancer-promoting pathway in mouse melanoma (B16F10) and breast (4T1) cancer cells, with emphasis on heparanase expression. We detected whether hinokitiol can elicit anti-metastatic effects on cancer cells via wound healing and Transwell assays. Besides, mice experiment was conducted to observe the impact of hinokitiol in vivo. Our results show that hinokitiol can inhibit the expression of heparanase by reducing the phosphorylation of protein kinase B (Akt) and extracellular regulated protein kinase (ERK). Furthermore, in vitro cell migration assay showed that heparanase downregulation by hinokitiol led to a decrease in metastatic activity which is consistent with the findings in the in vivo experiment.

Targeting Ubiquitin–Proteasome System With Copper Complexes for Cancer Therapy

“…Hinokitiol is a tropolone-based phenolic component isolated from Cupressaceae heartwood and its anticancer effects and antimicrobial activity have been well-documented ( Inoue et al, 2020 ; Wu et al, 2020 ). In addition, the hinokitiol copper complex (CuHK) has been confirmed as an inhibitor of the 19S DUB, but not the CT-like activity of the 20S proteasome ( Chen et al, 2017 ).…”

Hinokitiol Exhibits Antitumor Properties through Induction of ROS-Mediated Apoptosis and p53-Driven Cell-Cycle Arrest in Endometrial Cancer Cell Lines (Ishikawa, HEC-1A, KLE)

“…A large amount of the literature in the public domain has demonstrated the various biological properties of hinokitiol, including its neuroprotective activity [ 10 ], as well as its antibacterial [ 11 ] and anti-inflammatory [ 12 ] effects. In addition, hinokitiol has been shown to have antitumor potential against a variety of cancers; this potential involves reducing metastasis in 4T1 breast cancer cells [ 13 ], promoting apoptosis in A549 lung cancer cells [ 14 ], inducing senescence and autophagy in HeLa cervical cancer cells [ 15 ], disrupting androgen receptor signaling in LNCaP prostate carcinoma cells [ 16 ], and alleviating the migration ability [ 13 ] and melanogenesis in B16F10 melanoma cells [ 17 ]. It is worth mentioning that hinokitiol has the ability to inhibit tumor growth without causing damage to normal tissue; for example, hinokitiol simultaneously inhibits the growth of oral pathogens and oral squamous cell carcinoma cells without inducing toxicity in normal human oral keratinocytes [ 18 ].…”

Heparanase is a novel biomarker for immune infiltration and prognosis in breast cancer

“…Tumor growth, vascularization and recurrence were significantly reduced by inhibition the procoagulant activity of HPSE [ 41 ]. Furthermore, inhibition of HPSE expression reduced tumor metastasis by reducing extracellular regulated protein kinase (ERK) and phosphorylation of protein kinase B (Akt) [ 42 ].…”