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Growth inhibitory effect of polyunsaturated fatty acids (PUFAs) on colon cancer cells via their growth inhibitory metabolites and fatty acid composition changes.

Zhang C, Yu H, Ni X, Shen S, Das UN - PLoS ONE (2015)

Bottom Line: PUFAs and 5-FU inhibited growth of LoVo and RKO cells to the same extent at the doses used and produced significant alterations in their shape.As expected, higher concentrations of supplemented PUFAs were noted in the cells compared to control.All the PUFAs tested enhanced, while 5-FU decreased LXA4 formation in RKO cells; whereas GLA, AA, and 5-FU augmented while LA, ALA, EPA and DHA enhanced COX-2 expression in RKO cells.

View Article: PubMed Central - PubMed

Affiliation: College of Biosystems Engineering and Food Science, Zhejiang University, Hangzhou, 310058, PR China.

ABSTRACT

Background: Colorectal cancer is common. Polyunsaturated fatty acids (PUFAs) exert growth-inhibitory and pro-apoptotic effects on colon cancer cells. Metabolites of PUFAs such as prostaglandins (PGs), leukotrienes (LTs) and lipoxins (LXs) play a significant role in colon cancer.

Methods: Human colon cancer LoVo and RKO cells were cultured with different concentration of PUFAs and 5-fluorouracil (5-FU) in vitro. Cell morphological changes, fatty acid composition, formation of PGE2, LTB4 and LXA4 and expression of COX-2, ALOX5, PGD synthase (PGDS), microsomal prostaglandin E synthase (mPGES) were assessed in LoVo and RKO cells when supplemented with PUFAs and 5-FU.

Results: PUFAs and 5-FU inhibited growth of LoVo and RKO cells to the same extent at the doses used and produced significant alterations in their shape. As expected, higher concentrations of supplemented PUFAs were noted in the cells compared to control. LA, GLA, AA, ALA and EPA supplementation to LoVo cells suppressed production of PGE2, LTB4,and ALOX5, mPGES expression, but enhanced that of LXA4; whereas DHA enhanced PGE2 and LXA4 synthesis but decreased LTB4 formation and COX-2, ALOX5, mPGES expression. In contrast, 5-FU enhanced formation of PGE2, LTB4 and mPGES expression, but suppressed LXA4 synthesis and COX-2 expression. PGE2, LTB4 synthesis and ALOX5 expression was suppressed by LA, GLA, ALA and DHA; whereas AA, EPA and 5-FU enhanced PGE2 but paradoxically AA decreased and EPA and 5-FU enhanced LTB4 synthesis in RKO cells. All the PUFAs tested enhanced, while 5-FU decreased LXA4 formation in RKO cells; whereas GLA, AA, and 5-FU augmented while LA, ALA, EPA and DHA enhanced COX-2 expression in RKO cells.

Conclusions: Tumoricidal action of PUFAs on colorectal LoVo and RKO cancer cells in vitro was associated with increased formation of LXA4, decreased synthesis of PGE2 and LTB4 and suppressed expression of COX-2, ALOX5, mPGES, whereas 5-FU produced contrasting actions on these indices.

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Effect of ALA, DHA, EPA, LA, AA, GLA and 5-FU on the expression of PGE2/LXA4 in LoVo and RKO cells in vitro.Values in the same column with different letters are significantly different (p<0.05).
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pone.0123256.g009: Effect of ALA, DHA, EPA, LA, AA, GLA and 5-FU on the expression of PGE2/LXA4 in LoVo and RKO cells in vitro.Values in the same column with different letters are significantly different (p<0.05).

Mentions: AA, EPA and DHA form precursors not only to pro-inflammatory molecules PGs, TXs and LTs but also give rise to potent anti-inflammatory molecules LXs, resolvins, protectins, maresins and nitrolipids [9, 31, 32]. PGE2 and PGF2α and LTA4 and LTB4 are known to be produced in significantly higher amounts by tumor cells, which may enhance their motility and invasive capacity [33]. In contrast, LXA4 may promote apoptosis and inhibit growth of tumors by suppressing tumor angiogenesis by inhibiting the production of VEGF [34]. This suggests that balance between pro-inflammatory PGs, LTs and TXs and anti-inflammatory LXs, resolvins, protectins, maresins and nitrolipids (that are formed due to reaction between various PUFAs and nitric oxide and these compounds have anti-inflammatory actions) may determine the degree of proliferation and invasive capacity of tumor cells [8]. In addition, PGD2 can also inhibit cell proliferation and induce apoptosis in various cell types, including colon cancer cells [35]. In the present study, the expression of PGD synthase (a rate limiting enzyme that regulates the synthesis of prostaglandin D2) was found to be up-regulated by PUFAs (except for EPA and GLA) compared to control in LoVo. On the other hand, it was observed that majority of the PUFAs except DHA inhibited the release of PGE2, while all PUFAs inhibited LTB4 production but enhanced the synthesis and release of LXA4 in LoVo cells. Similarly, all PUFAs except AA and EPA inhibited PGE2 and LTB4 (except EPA) but enhanced the production of LXA4 in RKO cells (see Figs 5 and 6). Furthermore, it is noteworthy that DHA, EPA and AA induced significant increase in the secretion of LXA4 compared to other PUFAs suggesting that anticancer actions of these three PUFAs may due to their ability to enhance the formation of LXA4 in addition to suppressing PGE2 and LTB4 synthesis. This is evident from the data shown in Fig 9 wherein we calculated the PGE2/LXA4 ratio. All PUFAs reduced this ratio in LoVo cells compared to control except 5-FU, whereas AA, EPA (AA > EPA) and 5-FU increased this ratio in RKO cells. Thus, in general, all PUFAs enhanced the formation of LXA4 and decreased the synthesis of PGE2 and LTB4 tilting the balance more towards anti-inflammatory status. (Fig 9: Effect of ALA, DHA, EPA, LA, AA, GLA and 5-FU on the expression of PGE2/LXA4 in LoVo and RKO cells in vitro; Values in the same column with different letters are significantly different (p<0.05). A summary of the data obtained in the present study showing the changes that occurred as a result of the action of various PUFAs and 5-FU on the secretion of PGE2, LTB4, LXA4, ALOX5, COX-2, PGDS and mPGES activity in LoVo and RKO is given in Table 3 for easy reference. (Table 3: Summary of the effect of various PUFAs and 5-FU on the secretion of PGE2, LTB4, LXA4, ALOX5, COX-2, PGDS and mPGES activity in LoVo and RKO cells in vitro. N/D = Below detectable limits).


Growth inhibitory effect of polyunsaturated fatty acids (PUFAs) on colon cancer cells via their growth inhibitory metabolites and fatty acid composition changes.

Zhang C, Yu H, Ni X, Shen S, Das UN - PLoS ONE (2015)

Effect of ALA, DHA, EPA, LA, AA, GLA and 5-FU on the expression of PGE2/LXA4 in LoVo and RKO cells in vitro.Values in the same column with different letters are significantly different (p<0.05).
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4401647&req=5

pone.0123256.g009: Effect of ALA, DHA, EPA, LA, AA, GLA and 5-FU on the expression of PGE2/LXA4 in LoVo and RKO cells in vitro.Values in the same column with different letters are significantly different (p<0.05).
Mentions: AA, EPA and DHA form precursors not only to pro-inflammatory molecules PGs, TXs and LTs but also give rise to potent anti-inflammatory molecules LXs, resolvins, protectins, maresins and nitrolipids [9, 31, 32]. PGE2 and PGF2α and LTA4 and LTB4 are known to be produced in significantly higher amounts by tumor cells, which may enhance their motility and invasive capacity [33]. In contrast, LXA4 may promote apoptosis and inhibit growth of tumors by suppressing tumor angiogenesis by inhibiting the production of VEGF [34]. This suggests that balance between pro-inflammatory PGs, LTs and TXs and anti-inflammatory LXs, resolvins, protectins, maresins and nitrolipids (that are formed due to reaction between various PUFAs and nitric oxide and these compounds have anti-inflammatory actions) may determine the degree of proliferation and invasive capacity of tumor cells [8]. In addition, PGD2 can also inhibit cell proliferation and induce apoptosis in various cell types, including colon cancer cells [35]. In the present study, the expression of PGD synthase (a rate limiting enzyme that regulates the synthesis of prostaglandin D2) was found to be up-regulated by PUFAs (except for EPA and GLA) compared to control in LoVo. On the other hand, it was observed that majority of the PUFAs except DHA inhibited the release of PGE2, while all PUFAs inhibited LTB4 production but enhanced the synthesis and release of LXA4 in LoVo cells. Similarly, all PUFAs except AA and EPA inhibited PGE2 and LTB4 (except EPA) but enhanced the production of LXA4 in RKO cells (see Figs 5 and 6). Furthermore, it is noteworthy that DHA, EPA and AA induced significant increase in the secretion of LXA4 compared to other PUFAs suggesting that anticancer actions of these three PUFAs may due to their ability to enhance the formation of LXA4 in addition to suppressing PGE2 and LTB4 synthesis. This is evident from the data shown in Fig 9 wherein we calculated the PGE2/LXA4 ratio. All PUFAs reduced this ratio in LoVo cells compared to control except 5-FU, whereas AA, EPA (AA > EPA) and 5-FU increased this ratio in RKO cells. Thus, in general, all PUFAs enhanced the formation of LXA4 and decreased the synthesis of PGE2 and LTB4 tilting the balance more towards anti-inflammatory status. (Fig 9: Effect of ALA, DHA, EPA, LA, AA, GLA and 5-FU on the expression of PGE2/LXA4 in LoVo and RKO cells in vitro; Values in the same column with different letters are significantly different (p<0.05). A summary of the data obtained in the present study showing the changes that occurred as a result of the action of various PUFAs and 5-FU on the secretion of PGE2, LTB4, LXA4, ALOX5, COX-2, PGDS and mPGES activity in LoVo and RKO is given in Table 3 for easy reference. (Table 3: Summary of the effect of various PUFAs and 5-FU on the secretion of PGE2, LTB4, LXA4, ALOX5, COX-2, PGDS and mPGES activity in LoVo and RKO cells in vitro. N/D = Below detectable limits).

Bottom Line: PUFAs and 5-FU inhibited growth of LoVo and RKO cells to the same extent at the doses used and produced significant alterations in their shape.As expected, higher concentrations of supplemented PUFAs were noted in the cells compared to control.All the PUFAs tested enhanced, while 5-FU decreased LXA4 formation in RKO cells; whereas GLA, AA, and 5-FU augmented while LA, ALA, EPA and DHA enhanced COX-2 expression in RKO cells.

View Article: PubMed Central - PubMed

Affiliation: College of Biosystems Engineering and Food Science, Zhejiang University, Hangzhou, 310058, PR China.

ABSTRACT

Background: Colorectal cancer is common. Polyunsaturated fatty acids (PUFAs) exert growth-inhibitory and pro-apoptotic effects on colon cancer cells. Metabolites of PUFAs such as prostaglandins (PGs), leukotrienes (LTs) and lipoxins (LXs) play a significant role in colon cancer.

Methods: Human colon cancer LoVo and RKO cells were cultured with different concentration of PUFAs and 5-fluorouracil (5-FU) in vitro. Cell morphological changes, fatty acid composition, formation of PGE2, LTB4 and LXA4 and expression of COX-2, ALOX5, PGD synthase (PGDS), microsomal prostaglandin E synthase (mPGES) were assessed in LoVo and RKO cells when supplemented with PUFAs and 5-FU.

Results: PUFAs and 5-FU inhibited growth of LoVo and RKO cells to the same extent at the doses used and produced significant alterations in their shape. As expected, higher concentrations of supplemented PUFAs were noted in the cells compared to control. LA, GLA, AA, ALA and EPA supplementation to LoVo cells suppressed production of PGE2, LTB4,and ALOX5, mPGES expression, but enhanced that of LXA4; whereas DHA enhanced PGE2 and LXA4 synthesis but decreased LTB4 formation and COX-2, ALOX5, mPGES expression. In contrast, 5-FU enhanced formation of PGE2, LTB4 and mPGES expression, but suppressed LXA4 synthesis and COX-2 expression. PGE2, LTB4 synthesis and ALOX5 expression was suppressed by LA, GLA, ALA and DHA; whereas AA, EPA and 5-FU enhanced PGE2 but paradoxically AA decreased and EPA and 5-FU enhanced LTB4 synthesis in RKO cells. All the PUFAs tested enhanced, while 5-FU decreased LXA4 formation in RKO cells; whereas GLA, AA, and 5-FU augmented while LA, ALA, EPA and DHA enhanced COX-2 expression in RKO cells.

Conclusions: Tumoricidal action of PUFAs on colorectal LoVo and RKO cancer cells in vitro was associated with increased formation of LXA4, decreased synthesis of PGE2 and LTB4 and suppressed expression of COX-2, ALOX5, mPGES, whereas 5-FU produced contrasting actions on these indices.

Show MeSH
Related in: MedlinePlus