Ethoxysanguinarine inhibits viability and induces apoptosis of colorectal cancer cells by inhibiting CIP2A

Jin, Lan; Su, Yuan; Hong, Xing; Liu, Pengfei; Zhu, Beibei; Yu, Huiliang; Zhao, Xinhua; Qin, Shanshan; Xiong, Mengyuan; Liu, Ying; Luo, Zhiguo; Guo, Yang

doi:10.3892/ijo.2018.4323

Cited by 6 publications

(10 citation statements)

References 30 publications

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“…Traditional Chinese medicine, as an important source of medicine and therapeutics, plays a critical role in the treatment of numerous human diseases. Eth, an active natural compound, has been reported to possess potential anticancer activities by targeting the oncoprotein CIP2A (Liu et al, 2014;Jin et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

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Ethoxysanguinarine, a Novel Direct Activator of AMP-Activated Protein Kinase, Induces Autophagy and Exhibits Therapeutic Potential in Breast Cancer Cells

Wang

et al. 2020

Front. Pharmacol.

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Ethoxysanguinarine (Eth) is a benzophenanthridine alkaloid extracted from Macleaya cordata (Willd) R. Br. It possesses antibacterial and antiviral activities and offers therapeutic benefits for the treatment of respiratory syndrome virus-induced cytopathic effects. However, the effect of Eth on human tumors and its pharmacological effects remain to be elucidated, together with its cellular target. Here, we examined the effects of Eth on breast cancer (BC) cells. We found that at low doses, Eth strongly inhibited the viability of BC cell lines and induced autophagy. Mechanistic studies showed that Eth induced autophagy by upregulating the activity of the AMP-activated protein kinase (AMPK). The AMPK inhibitor compound C significantly attenuated Eth-induced autophagy and inhibited proliferation. Meanwhile, the AMPK activator metformin significantly enhanced Eth-induced autophagy and inhibited proliferation. Computational docking and affinity assays showed that Eth directly interacted with the allosteric drug and metabolite site of AMPK to stabilize its activation. AMPK was less activated in tumor samples compared to normal breast tissues and was inversely associated with the prognosis of the patients. Moreover, Eth exhibited potent anti-BC activity in nude mice and favorable pharmacokinetics in rats. These characteristics render Eth as a promising candidate drug for further development and for designing new effective AMPK activators.

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Section: Discussionmentioning

confidence: 99%

“…There are limited reports on the effect of Eth on cancer cells. In 2018, we revealed that Eth can induce inhibitory effects and downregulate the oncoprotein CIP2A (cancerous inhibitor of protein phosphatase 2A) in colorectal cancer cells (Jin et al, 2018). The effect and mechanism of Eth in other cancer types needs investigation.…”

Section: Introductionmentioning

confidence: 99%

Ethoxysanguinarine, a Novel Direct Activator of AMP-Activated Protein Kinase, Induces Autophagy and Exhibits Therapeutic Potential in Breast Cancer Cells

Wang

et al. 2020

Front. Pharmacol.

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“…Escape from apoptosis is an important feature of cancer progression and drug resistance, and the activation of apoptosis has become another important strategy for cancer treatment [35]. Casp-3 is an effector of extrinsic and intrinsic apoptotic signaling [10]. We showed that CuB induced a reduction in the levels of pro-casp-8 and pro-casp-3 and induced the proteolysis of PARP (Figure 2D), which suggested that casp-8 and casp-3 were activated.…”

Section: Discussionmentioning

confidence: 99%

“…In the past 10 years, the cancerous inhibitor of protein phosphatase 2A (CIP2A) has been increasingly recognized as a key oncoprotein in several human malignancies, including myeloma [6], breast cancer [7], gastric cancer [8], glioma [9], and colorectal cancer [10]. Previous independent studies have shown that abnormal CIP2A overexpression is associated with tumor growth, anti-apoptotic effects, drug resistance, metastasis, and poor prognosis of the malignant tumors mentioned above.…”

Section: Introductionmentioning

confidence: 99%

Cucurbitacin B Induces the Lysosomal Degradation of EGFR and Suppresses the CIP2A/PP2A/Akt Signaling Axis in Gefitinib-Resistant Non-Small Cell Lung Cancer

Liu

Xiang

et al. 2019

Molecules

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Non-small cell lung cancer (NSCLC) patients carrying an epidermal growth factor receptor (EGFR) mutation are initially sensitive to EGFR-tyrosine kinase inhibitors (TKIs) treatment, but soon develop an acquired resistance. The treatment effect of EGFR-TKIs-resistant NSCLC patients still faces challenges. Cucurbitacin B (CuB), a triterpene hydrocarbon compound isolated from plants of various families and genera, elicits anticancer effects in a variety of cancer types. However, whether CuB is a viable treatment option for gefitinib-resistant (GR) NSCLC remains unclear. Here, we investigated the anticancer effects and underlying mechanisms of CuB. We report that CuB inhibited the growth and invasion of GR NSCLC cells and induced apoptosis. The inhibitory effect of CuB occurred through its promotion of the lysosomal degradation of EGFR and the downregulation of the cancerous inhibitor of protein phosphatase 2A/protein phosphatase 2A/Akt (CIP2A/PP2A/Akt) signaling axis. CuB and cisplatin synergistically inhibited tumor growth. A xenograft tumor model indicated that CuB inhibited tumor growth in vivo. Immunohistochemistry results further demonstrated that CuB decreased EGFR and CIP2A levels in vivo. These findings suggested that CuB could suppress the growth and invasion of GR NSCLC cells by inducing the lysosomal degradation of EGFR and by downregulating the CIP2A/PP2A/Akt signaling axis. Thus, CuB may be a new drug candidate for the treatment of GR NSCLC.

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“…Cancerous inhibitor of protein phosphatase 2A (CIP2A) is an endogenous protein phosphatase 2A (PP2A) inhibitor and Myc stabilizer, which is reported to promote malignant cell transformation and tumor growth [4]. Generally, CIP2A was expressed at a low level in normal tissues [5–8].…”

Section: Introductionmentioning

confidence: 99%

miR-548b-3p Regulates Proliferation, Apoptosis, and Mitochondrial Function by Targeting CIP2A in Hepatocellular Carcinoma

Lin

Wang

2018

BioMed Research International

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The roles of miR-548b-3p in the progression of hepatocellular carcinoma (HCC) remain undiscovered. This study aims to explore the roles and mechanisms of miR-548b-3p in HCC. Using TCGA database, we found that miR-548b-3p expression was lower in HCC compared to the normal tissues, which was further confirmed by RT-qPCR of 20 cases of surgically resected HCC and corresponding normal tissues. miR-548b-3p mimic and inhibitor were transfected into Huh7 and SK-Hep-1 cells, respectively. MTT, colony formation, and cell cycle assays showed that miR-548b-3p mimic suppressed cell growth and G1/S cell cycle transition. In contrast, miR-548b-3p inhibitor facilitated cell growth and cell cycle transition. miR-548b-3p mimic also increased cisplatin sensitivity by upregulating apoptosis rate. JC-1 staining showed that miR-548b-3p mimic downregulated mitochondrial membrane potential, while miR-548b-3p inhibitor showed the opposite effects in SK-Hep-1 cells. Using prediction software, we found that CIP2A was on the target list of miR-548b-3p. miR-548b-3p mimic downregulated CIP2A and its downstream target protein c-Myc. Luciferase reporter assay demonstrated that CIP2A was as a direct target of miR-548b-3p. CIP2A depletion partly reduced the effect of miR-548b-3p mimic/inhibitor on c-Myc. CIP2A depletion also reduced the effect of miR-548b-3p mimic/inhibitor on proliferation. In conclusion, our data demonstrated that miR-548b-3p was downregulated in HCC. miR-548b-3p regulates proliferation, apoptosis and mitochondrial function by targeting CIP2A in HCC.

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Ethoxysanguinarine inhibits viability and induces apoptosis of colorectal cancer cells by inhibiting CIP2A

Cited by 6 publications

References 30 publications

Ethoxysanguinarine, a Novel Direct Activator of AMP-Activated Protein Kinase, Induces Autophagy and Exhibits Therapeutic Potential in Breast Cancer Cells

Ethoxysanguinarine, a Novel Direct Activator of AMP-Activated Protein Kinase, Induces Autophagy and Exhibits Therapeutic Potential in Breast Cancer Cells

Cucurbitacin B Induces the Lysosomal Degradation of EGFR and Suppresses the CIP2A/PP2A/Akt Signaling Axis in Gefitinib-Resistant Non-Small Cell Lung Cancer

miR-548b-3p Regulates Proliferation, Apoptosis, and Mitochondrial Function by Targeting CIP2A in Hepatocellular Carcinoma

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