Carvacrol induces cytotoxicity in human cervical cancer cells but causes cisplatin resistance: Involvement of MEK–ERK activation

Potočnjak, Iva; Gobin, Ivana; Domitrović, Robert

doi:10.1002/ptr.6048

Cited by 49 publications

(35 citation statements)

References 43 publications

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“…Many researches about chemotherapeutic drugs 41,42 , tumor-related gene 43 , microRNA 38 , and LncRNA 44 have shown multiple effects on cervical cancer by regulation of MAPK signaling pathway. However, most of the studies agreed that phosphorylation of ERK 38,45 was upregulated to promote the proliferation or (and) suppress the apoptosis 33,46 of cervical cancer, while evidences showed contrary effect in this study (Fig.…”

Section: Discussionmentioning

confidence: 99%

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A novel function of IMPA2, plays a tumor-promoting role in cervical cancer

et al. 2020

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Discovery of genes and molecular mechanism involved in cervical cancer development would promote the prevention and treatment. By comparing gene expression profiles of cervical carcinoma in situ (CCIS) and adjacent normal tissues, we identified a potential cancer-promoting gene, IMPA2. This study aimed to elucidate the role of IMPA2 and underlying molecular mechanisms in cervical cancer progression. To do this expression of IMPA2 was compared between human cervical cancer and corresponding adjacent normal cervical tissues firstly. CCK-8 assay, clone formation assay, wound healing assay, transwell assay, and tumor formation in nude mice were performed to demonstrate the effect of IMPA2 in cervical cancer proliferation and metastasis. Further proteomic profiling and western blotting explored the molecular pathway involved in the IMPA2-regulating process. The results showed that IMPA2 gene expression was upregulated in cervical cancer. Consistently, silencing of IMPA2 suppressed tumor formation in BALB/c nude mice. Short hairpin RNA (shRNA)-mediated IMPA2 silencing significantly inhibited proliferation and colony-forming abilities of cervical cancer cells, while IMPA2 overexpression had little impact. Also, IMPA2 silencing suppressed cellular migration, but overexpression promoted migration. Proteomics analysis revealed the involvement of mitogen-activated protein kinase (MAPK) pathway in tumor-promoting action of IMPA2. Significantly, the inhibition of IMPA2 activated ERK phosphorylation, and its inhibitory effects can be restored by using selective ERK inhibitor, FR180204. In conclusion, IMPA2 acts as an oncogene in the proliferation and migration of cervical cancer. IMPA2 downregulated ERK phosphorylation to promote cervical cancer. These findings identify a new mechanism underlying cervical cancer and suggest a regulating effect of IMPA2 in MAPK signaling pathway.

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Section: Discussionmentioning

confidence: 99%

“…Therefore, we thought ERK cannot regulate tumorigenesis directly. Previous studies demonstrated that activation of ERK MAPK could also induce cytotoxicity or tumor inhibition in some cancers 19,41,47 . Some studies revealed that activation of ERK could promote apoptosis progress 48,49 .…”

Section: Discussionmentioning

confidence: 99%

A novel function of IMPA2, plays a tumor-promoting role in cervical cancer

et al. 2020

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“…Numerous studies have been conducted to unveil the significant outcomes of isoprenoid-based manipulations of the mevalonate pathway and HMGCR in cancer cells. γ-Tocotrienol at 0–30 μM downregulated HMGCR, membrane H-, K-, and N-Ras, and Raf-1, p-AKT, and p-ERK in HL-60 cells (Chen et al, 2015), adding to a long list of in vitro and in vivo studies showing isoprenoid-mediated suppression of the growth of cancer cells including those of blood (Shoff et al, 1991; Melnykovych et al, 1992; Mo and Elson, 1999; Lee et al, 2015), breast (Iqbal et al, 2004; Pierpaoli et al, 2010, 2013; Gomide et al, 2013; Ding et al, 2017), cervix (Yazlovitskaya and Melnykovych, 1995; Xu et al, 2017; Potocnjak et al, 2018), colon (Mo and Elson, 1999; Gomide et al, 2013, 2016), liver (Wada et al, 2005; Crespo et al, 2013; Scolastici et al, 2014; Rodenak-Kladniew et al, 2018), lung (Mo and Elson, 1999; Wada et al, 2005; Gomide et al, 2013; Galle et al, 2014), mouth (Liang et al, 2013; Madankumar et al, 2013), pancreas (Hussein and Mo, 2009; Fernandes et al, 2013), prostate (Mo and Elson, 2004; Sundin et al, 2012; Fernandes et al, 2013; Jones et al, 2013; Yeganehjoo et al, 2017), skin (Mo et al, 2000; McAnally et al, 2007; Chang et al, 2009; Chaudhary et al, 2013), and stomach (Dong et al, 2013; Liu et al, 2013). Concomitantly, isoprenoids induce cell cycle arrest and apoptosis in the tumor cells (Mo and Elson, 1999, 2004; Dong et al, 2013; Jones et al, 2013; Yeganehjoo et al, 2017; Rodenak-Kladniew et al, 2018; Sailo et al, 2018).…”

Section: Isoprenoids and Their Mechanisms Of Actionmentioning

confidence: 99%

The Potential of Isoprenoids in Adjuvant Cancer Therapy to Reduce Adverse Effects of Statins

Jeter

Bachmann

et al. 2019

Front. Pharmacol.

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The mevalonate pathway provides sterols for membrane structure and nonsterol intermediates for the post-translational modification and membrane anchorage of growth-related proteins, including the Ras, Rac, and Rho GTPase family. Mevalonate-derived products are also essential for the Hedgehog pathway, steroid hormone signaling, and the nuclear localization of Yes-associated protein and transcriptional co-activator with PDZ-binding motif, all of which playing roles in tumorigenesis and cancer stem cell function. The phosphatidylinositol-4,5-bisphosphate 3-kinase-AKT-mammalian target of rapamycin complex 1 pathway, p53 with gain-of-function mutation, and oncoprotein MYC upregulate the mevalonate pathway, whereas adenosine monophosphate-activated protein kinase and tumor suppressor protein RB are the downregulators. The rate-limiting enzyme, 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), is under a multivalent regulation. Sterol regulatory element binding protein 2 mediates the sterol-controlled transcriptional downregulation of HMGCR. UbiA prenyltransferase domain-containing protein-1 regulates the ubiquitination and proteasome-mediated degradation of HMGCR, which is accelerated by 24, 25-dihydrolanosterol and the diterpene geranylgeraniol. Statins, competitive inhibitors of HMGCR, deplete cells of mevalonate-derived intermediates and consequently inhibit cell proliferation and induce apoptosis. Clinical application of statins is marred by dose-limiting toxicities and mixed outcomes on cancer risk, survival and mortality, partially resulting from the statin-mediated compensatory upregulation of HMGCR and indiscriminate inhibition of HMGCR in normal and tumor cells. Tumor HMGCR is resistant to the sterol-mediated transcriptional control; consequently, HMGCR is upregulated in cancers derived from adrenal gland, blood and lymph, brain, breast, colon, connective tissue, embryo, esophagus, liver, lung, ovary, pancreas, prostate, skin, and stomach. Nevertheless, tumor HMGCR remains sensitive to isoprenoid-mediated degradation. Isoprenoids including monoterpenes (carvacrol, L-carvone, geraniol, perillyl alcohol), sesquiterpenes (cacalol, farnesol, β-ionone), diterpene (geranylgeranyl acetone), “mixed” isoprenoids (tocotrienols), and their derivatives suppress the growth of tumor cells with little impact on non-malignant cells. In cancer cells derived from breast, colon, liver, mesothelium, prostate, pancreas, and skin, statins and isoprenoids, including tocotrienols, geraniol, limonene, β-ionone and perillyl alcohol, synergistically suppress cell proliferation and associated signaling pathways. A blend of dietary lovastatin and δ-tocotrienol, each at no-effect doses, suppress the growth of implanted murine B16 melanomas in C57BL6 mice. Isoprenoids have potential as adjuvant agents to reduce the toxicities of statins in cancer prevention or therapy.

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“…Studies have shown that carvacrol is effective against Salmonella and Escherichia coli, Campylobacter jejuni and Listeria monocytogenes (Obaidat and Frank, 2009;Van et al, 2012;Upadhyay et al, 2012). Salmonella colonies on celery were destroyed by carvacrol (Ravishankar et al, 2010). Candida albicans taken from patients using dentures were tested against carvacrol.…”

Section: Effects Of Carvacrol and Carvacrolmentioning

confidence: 99%

Areas of Utilization of Orıganum acutidens (HAND.-MAZZ.) Ietswaart and Carvacrol

Karagöz¹,

Karagöz²

2019

Int.J.Curr.Res.Aca.Rev.

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Article InfoOriganum acutidens (Hand.-Mazz.) Ietswaart is an endemic plant growing in the eastern part of Turkey. Origanum acutidens, rich in rosmarinic acid, has a high antioxidant effect. The essential oil of this plant is rich in carvacrol. The plant has chemotypes containing up to 90% carvacrol. Carvacrol also has a comprehensive range of uses from health to food. According to results obtained from previous studies, carvacrol has a lethal effect against some cancer cells. Furthermore, carvacrol has antifungal and antibacterial effects and it is lethal for some agriculturally harmful insect species. In this study, we have compiled the details of various research findings related to the morphology, natural distribution and synonymous of Origanum acutidens, its karyological and histological features, its content and yield of essential oil and its pharmacological property and the effects of carvacrol based on an exhaustive literature review. Such knowledge could contribute to the design of new and more effective technologies for the increased use and in the number of plant-based drugs for plant and human health. Using alternative and integrative strategies such as phytochemicals against harmful insect families, bacteria and fungi in agricultural areas and storage conditions are among current necessities. In addition, this review may contribute to provide a new and additional perspective on cancer treatment by combining the finding that the carvacrol in the essential oil of Origanum acutidensis effective against cancer cells.

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Carvacrol induces cytotoxicity in human cervical cancer cells but causes cisplatin resistance: Involvement of MEK–ERK activation

Cited by 49 publications

References 43 publications

A novel function of IMPA2, plays a tumor-promoting role in cervical cancer

A novel function of IMPA2, plays a tumor-promoting role in cervical cancer

The Potential of Isoprenoids in Adjuvant Cancer Therapy to Reduce Adverse Effects of Statins

Areas of Utilization of Orıganum acutidens (HAND.-MAZZ.) Ietswaart and Carvacrol

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