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Dual Regulation of Cell Death and Cell Survival upon Induction of Cellular Stress by Isopimara-7,15-Dien-19-Oic Acid in Cervical Cancer, HeLa Cells In vitro.

Abu N, Yeap SK, Pauzi AZ, Akhtar MN, Zamberi NR, Ismail J, Zareen S, Alitheen NB - Front Pharmacol (2016)

Bottom Line: The Fritillaria imperialis is an ornamental flower that can be found in various parts of the world including Iraq, Afghanistan, Pakistan, and the Himalayas.Based on the results, Isopimara-7,15-Dien-19-Oic acid simultaneously induced cell death and promoted cell survival.Collectively, Isopimara-7,15-Dien-19-Oic Acid managed to induce cellular stress in HeLa cells and activate several anti- and pro survival pathways.

View Article: PubMed Central - PubMed

Affiliation: Department of Cell and Molecular Biology, Faculty of Biotechnology and Biomolecular Sciences, Universiti Putra Malaysia Serdang, Malaysia.

ABSTRACT
The Fritillaria imperialis is an ornamental flower that can be found in various parts of the world including Iraq, Afghanistan, Pakistan, and the Himalayas. The use of this plant as traditional remedy is widely known. This study aims to unveil the anti-cancer potentials of Isopimara-7,15-Dien-19-Oic Acid, extracted from the bulbs of F. imperialis in cervical cancer cell line, HeLa cells. Flow cytometry analysis of cell death, gene expression analysis via cDNA microarray and protein array were performed. Based on the results, Isopimara-7,15-Dien-19-Oic acid simultaneously induced cell death and promoted cell survival. The execution of apoptosis was apparent based on the flow cytometry results and regulation of both pro and anti-apoptotic genes. Additionally, the regulation of anti-oxidant genes were up-regulated especially thioredoxin, glutathione and superoxide dismutase- related genes. Moreover, the treatment also induced the activation of pro-survival heat shock proteins. Collectively, Isopimara-7,15-Dien-19-Oic Acid managed to induce cellular stress in HeLa cells and activate several anti- and pro survival pathways.

No MeSH data available.


Related in: MedlinePlus

Proposed schematic of the mechanism of action of DIA in HeLa cells by regulating both the anti- and pro-survival pathways.
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Figure 8: Proposed schematic of the mechanism of action of DIA in HeLa cells by regulating both the anti- and pro-survival pathways.

Mentions: The expression of NRF2-related genes in DIA-induced HeLa cells is significant and this may give way to the underlying mechanism of DIA. The NRF2 is the key player to several antioxidant pathways including the iron sequestration pathway, quinone detoxification, GSH production, and thioredoxin production (Nguyen et al., 2009; Gorrini et al., 2013; Ma, 2013). Once the NRF2 is stimulated it will further activate phase II detoxification enzymes (Kwak and Kensler, 2010). The thioredoxin (trx) and glutathione pathway are among the antioxidants pathway that can cross-talk with multiple other pathways and with each other (Brigelius-Flohé et al., 2012; Isaac Harris et al., 2014; Lu and Holmgren, 2014; Vriend and Reiter, 2015). Both systems are dependent on NADPH and are involved in the antioxidant defensive mechanism, redox regulation and cell growth (Arnér and Holmgren, 2006; Peng et al., 2012, 2014). There are various ways as to how the thioredoxin system contributes toward the progression of cancer (Arnér and Holmgren, 2006). There are two trx systems in the mammalian cells; the cytosolic trx and mitochondrial trx (Lu and Holmgren, 2014). Both the cytosolic and mitochondrial trx systems are dependent on peroxidases and eventually involved in the redox regulation (Lu and Holmgren, 2014). Thioredoxin reductase 1 is known to be overexpressed in most malignant cancer cells (Miyazaki et al., 1998; Yoo et al., 2006; Karlenius and Tonissen, 2010). In fact, besides being involved in the defensive mechanism of cells, thioredoxin peroxidase (TRx) has been reported to inhibit apoptosis by interfering with p53 and p21 (Zhang et al., 1997; Ueno et al., 1999; Brigelius-Flohé et al., 2012). Targeting players of the thioredoxin pathway such as thioredoxin reductase, peroxidase or thioredoxin has been an interest for cancer therapy (Arnér and Holmgren, 2006; Lu et al., 2007; Karlenius and Tonissen, 2010; Penney and Roy, 2013). Moreover, in most cancer cells, the level of GSH is often upregulated and can contribute to the drug-resistance mechanism (Balendiran et al., 2004; Traverso et al., 2013). GSH is a non-protein molecule that has several important physiological properties (Balendiran et al., 2004). Moreover, it is known that GSH can contribute toward the initiation of cancer. In phase II detoxification process, GST plays an important role as it assists in the conjugation of GSH with different cancer-promoting electrophiles (Balendiran et al., 2004). The high levels of GSH and GST has become one of the important properties in various types of cancer (Balendiran et al., 2004). Besides GSH, the level of SOD was also increased in DIA-treated cells. SOD is known to be higher in cancer cells than normal cells (Oberley and Buettner, 1979). The role of SOD as an antioxidant is by converting the radical O2 to the less radical H2O2 (Matés, 2000; Kowald and Klipp, 2004; Valko et al., 2006). Catalase, another antioxidant enzyme will later on convert the produced H2O2 to water and oxygen (Matés, 2000; Kowald and Klipp, 2004; Valko et al., 2006;). Additionally, the GPx enzyme will also convert H2O2 to water and GSSG (Matés, 2000; Valko et al., 2006). Another important phase II detoxification enzyme is the pro-survival HMOX-1, which is heavily involved in the inactivation of the pro-oxidant heme to ferrous iron, carbon monoxide and bilirubin (Lau et al., 2008; Yim et al., 2011). Activation of heat shock protein and antioxidant mechanism by this diterpene may protect the cancer cell and thus reduce the killing efficacy of DIA. Overall, Figure 8 summarizes the proposed schematic of mechanism of action of DIA in HeLa cells.


Dual Regulation of Cell Death and Cell Survival upon Induction of Cellular Stress by Isopimara-7,15-Dien-19-Oic Acid in Cervical Cancer, HeLa Cells In vitro.

Abu N, Yeap SK, Pauzi AZ, Akhtar MN, Zamberi NR, Ismail J, Zareen S, Alitheen NB - Front Pharmacol (2016)

Proposed schematic of the mechanism of action of DIA in HeLa cells by regulating both the anti- and pro-survival pathways.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4814465&req=5

Figure 8: Proposed schematic of the mechanism of action of DIA in HeLa cells by regulating both the anti- and pro-survival pathways.
Mentions: The expression of NRF2-related genes in DIA-induced HeLa cells is significant and this may give way to the underlying mechanism of DIA. The NRF2 is the key player to several antioxidant pathways including the iron sequestration pathway, quinone detoxification, GSH production, and thioredoxin production (Nguyen et al., 2009; Gorrini et al., 2013; Ma, 2013). Once the NRF2 is stimulated it will further activate phase II detoxification enzymes (Kwak and Kensler, 2010). The thioredoxin (trx) and glutathione pathway are among the antioxidants pathway that can cross-talk with multiple other pathways and with each other (Brigelius-Flohé et al., 2012; Isaac Harris et al., 2014; Lu and Holmgren, 2014; Vriend and Reiter, 2015). Both systems are dependent on NADPH and are involved in the antioxidant defensive mechanism, redox regulation and cell growth (Arnér and Holmgren, 2006; Peng et al., 2012, 2014). There are various ways as to how the thioredoxin system contributes toward the progression of cancer (Arnér and Holmgren, 2006). There are two trx systems in the mammalian cells; the cytosolic trx and mitochondrial trx (Lu and Holmgren, 2014). Both the cytosolic and mitochondrial trx systems are dependent on peroxidases and eventually involved in the redox regulation (Lu and Holmgren, 2014). Thioredoxin reductase 1 is known to be overexpressed in most malignant cancer cells (Miyazaki et al., 1998; Yoo et al., 2006; Karlenius and Tonissen, 2010). In fact, besides being involved in the defensive mechanism of cells, thioredoxin peroxidase (TRx) has been reported to inhibit apoptosis by interfering with p53 and p21 (Zhang et al., 1997; Ueno et al., 1999; Brigelius-Flohé et al., 2012). Targeting players of the thioredoxin pathway such as thioredoxin reductase, peroxidase or thioredoxin has been an interest for cancer therapy (Arnér and Holmgren, 2006; Lu et al., 2007; Karlenius and Tonissen, 2010; Penney and Roy, 2013). Moreover, in most cancer cells, the level of GSH is often upregulated and can contribute to the drug-resistance mechanism (Balendiran et al., 2004; Traverso et al., 2013). GSH is a non-protein molecule that has several important physiological properties (Balendiran et al., 2004). Moreover, it is known that GSH can contribute toward the initiation of cancer. In phase II detoxification process, GST plays an important role as it assists in the conjugation of GSH with different cancer-promoting electrophiles (Balendiran et al., 2004). The high levels of GSH and GST has become one of the important properties in various types of cancer (Balendiran et al., 2004). Besides GSH, the level of SOD was also increased in DIA-treated cells. SOD is known to be higher in cancer cells than normal cells (Oberley and Buettner, 1979). The role of SOD as an antioxidant is by converting the radical O2 to the less radical H2O2 (Matés, 2000; Kowald and Klipp, 2004; Valko et al., 2006). Catalase, another antioxidant enzyme will later on convert the produced H2O2 to water and oxygen (Matés, 2000; Kowald and Klipp, 2004; Valko et al., 2006;). Additionally, the GPx enzyme will also convert H2O2 to water and GSSG (Matés, 2000; Valko et al., 2006). Another important phase II detoxification enzyme is the pro-survival HMOX-1, which is heavily involved in the inactivation of the pro-oxidant heme to ferrous iron, carbon monoxide and bilirubin (Lau et al., 2008; Yim et al., 2011). Activation of heat shock protein and antioxidant mechanism by this diterpene may protect the cancer cell and thus reduce the killing efficacy of DIA. Overall, Figure 8 summarizes the proposed schematic of mechanism of action of DIA in HeLa cells.

Bottom Line: The Fritillaria imperialis is an ornamental flower that can be found in various parts of the world including Iraq, Afghanistan, Pakistan, and the Himalayas.Based on the results, Isopimara-7,15-Dien-19-Oic acid simultaneously induced cell death and promoted cell survival.Collectively, Isopimara-7,15-Dien-19-Oic Acid managed to induce cellular stress in HeLa cells and activate several anti- and pro survival pathways.

View Article: PubMed Central - PubMed

Affiliation: Department of Cell and Molecular Biology, Faculty of Biotechnology and Biomolecular Sciences, Universiti Putra Malaysia Serdang, Malaysia.

ABSTRACT
The Fritillaria imperialis is an ornamental flower that can be found in various parts of the world including Iraq, Afghanistan, Pakistan, and the Himalayas. The use of this plant as traditional remedy is widely known. This study aims to unveil the anti-cancer potentials of Isopimara-7,15-Dien-19-Oic Acid, extracted from the bulbs of F. imperialis in cervical cancer cell line, HeLa cells. Flow cytometry analysis of cell death, gene expression analysis via cDNA microarray and protein array were performed. Based on the results, Isopimara-7,15-Dien-19-Oic acid simultaneously induced cell death and promoted cell survival. The execution of apoptosis was apparent based on the flow cytometry results and regulation of both pro and anti-apoptotic genes. Additionally, the regulation of anti-oxidant genes were up-regulated especially thioredoxin, glutathione and superoxide dismutase- related genes. Moreover, the treatment also induced the activation of pro-survival heat shock proteins. Collectively, Isopimara-7,15-Dien-19-Oic Acid managed to induce cellular stress in HeLa cells and activate several anti- and pro survival pathways.

No MeSH data available.


Related in: MedlinePlus