Salidroside ameliorated hypoxia‐induced tumorigenesis of BxPC‐3 cells via downregulating hypoxia‐inducible factor (HIF)‐1α and LOXL2

Abstract

Herein, we found that salidroside suppressed hypoxia‐inducible factor 1 alpha (HIF‐1α) and lysyl oxidase‐like protein 2 (LOXL2) within human pancreatic cancer BxPC‐3 cells cultured both under normoxia and hypoxia condition. To investigate the effect of salidroside on tumorigenesis of BxPC‐3 cells and whether HIF‐1α and LXCL2 were involved in this process, cells transfected with or without LOXL2 overexpression vector, were treated with 50 μg/mL of salidroside or 50 μM of KC7F2 (a HIF‐1α inhibitor) under hypoxia. Cell viability and invasion were assessed using CCK‐8 and Transwell chamber assay, respectively. Expression of E‐cadherin and matrix metalloproteinase 2/9 (MMP 2/9) was determined, by Western blot analysis, to assess cell mobility at molecular levels. We confirmed that hypoxia increased LOXL2 and induced tumorigenesis of BxPC‐3 cells, as evidenced by promoted cell proliferation and invasion, enhanced MMP2/9 while reduced E‐cadherin. Interestingly, hypoxia‐induced carcinogenesis was significantly retarded by both salidroside and KC7F2, however, enhanced with LOXL2 overexpression. Besides, salidroside and KC7F2 reduced LOXL2, and reversed the tumorigenesis of BxPC‐3 cells induced by LOXL2 overexpression. Given the inhibitory effect of salidroside on HIF‐1α expression, our data suggested that: (1) LOXL2 was the mechanism, whereby salidroside and KC7F2 showed inhibitory effect on cancer progression of BxPC‐3 cells; (2) salidroside exerted its anticancer effect, most likely, by a HIF‐1α/LOXL2 pathway. In conclusion, salidroside was a novel therapeutic drug in pancreatic cancer, and downregulation of HIF‐1α and LXCL2 was the underlying mechanism.

Salidroside Promotes Sensitization to Doxorubicin in Human Cancer Cells by Affecting the PI3K/Akt/HIF Signal Pathway and Inhibiting the Expression of Tumor-Resistance-Related Proteins

“…The underlying mechanism of chemosensitization activity of Sal in the HeLa-ADR cell line was investigated by Western blotting. Previous studies suggest that Sal regulates hypoxia-related pathways. ,, The heterodimeric transcription factor hypoxia-inducible factor-1 (HIF-1), composed of two subunits (HIF-1α and HIF-1β), is the major regulator of hypoxia-activated genes and is known to play a key role in the progression of tumor multidrug resistance (MDR) . In this study, we found a significant increase in HIF-1α expression in the HeLa-ADR cells (Figure A), which can be attributed to the DOX resistance.…”

Roles of Lysyl Oxidase Family Members in the Tumor Microenvironment and Progression of Liver Cancer

“…The combination of DS and BAPN exerts a superior effect compared to DS or BAPN alone [ 100 ]. In addition, salidroside, a phenylpropanoid glycoside isolated from Rhodiola rosea L, down-regulates the mRNA expression level of LOX, LOXL1-4, and HIF-1α in a dose-dependent manner in pancreatic cancer cells [ 101 ]; thereby, the invasive activity of cancer cells, xenograft tumor growth, and distal metastasis can be hindered by treatment with salidroside [ 101 ]. Further studies have indicated that Escin Ia, belonging to a subclass of the saponin fraction of Aesculus chinensis Bunge fruits (SFAC), acts towards the down-regulation of LOXL2 and the inhibition of the metastatic behavior of triple-negative breast cancer in vitro and in vivo [ 102 ].…”

Retracted : Salidroside from Rhodiola wallichiana var. cholaensis reverses insulin resistance and stimulates the GLP‐1 secretion by alleviating ROS‐mediated activation of MAPKs signaling pathway and mitigating apoptosis

“…cholaensis . The pharmacological effects of salidroside include, but not limited to, anti‐cancer (Rong et al, 2020), anti‐inflammatory (Pu et al, 2020), anti‐hypoxia (Chen, Kou, Lu, & Pu, 2020), and anti‐oxidative properties (Liu et al, 2020). Recent pieces of evidence demonstrated that salidroside has also been considered as a potential therapeutic drug for diabetes because of its beneficial action in diabetic rodent models (Feng, Liu, Gao, Geng, & Dai, 2019).…”