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Targeting sphingosine kinase 2 (SphK2) by ABC294640 inhibits colorectal cancer cell growth in vitro and in vivo.

Xun C, Chen MB, Qi L, Tie-Ning Z, Peng X, Ning L, Zhi-Xiao C, Li-Wei W - J. Exp. Clin. Cancer Res. (2015)

Bottom Line: Moreover, a low concentration of ABC294640 sensitized the activity of 5-FU and cisplatin in vitro.In vivo, ABC294640 oral administration dramatically inhibited HT-29 xenografts growth in nude mice.Targeting of SphK2 by ABC294640 potently inhibits CRC cell growth both in vitro and in vivo, ABC294640 could be developed as a novel therapeutic for the treatment of CRC.

View Article: PubMed Central - PubMed

Affiliation: Department of Oncology, Shanghai General Hospital, Shanghai Jiaotong University, 100 Haining Road, Shanghai, Hongkou District, 200080, China. caixunshanghai2@163.com.

ABSTRACT

Background: Colorectal cancer (CRC) is a major health problem in China and around the world. It is one of the leading causes of cancer-related deaths. Research groups are thus searching for novel and more efficient anti-CRC agents.

Results: Here we demonstrated that ABC294640, a novel SphK2 inhibitor, induced growth inhibition and apoptosis in transformed and primary CRC cells. The SphK activity was remarkably inhibited by ABC294640, accompanied by sphingosine-1-phosphate (S1P) depletion and ceramide incensement in CRC cells. Exogenously-added S1P inhibited ABC294640-induced HT-29 cell lethality. While C6 ceramide and SphK1 inhibitor SKI-II facilitated ABC294640-induced cytotoxicity against HT-29 cells. ABC294640 inhibited AKT-S6K1, but activated JNK signaling in transformed and primary CRC cells. JNK inhibitors (SP600125 and JNKi-II) alleviated ABC294640-induced CRC cell apoptosis. Moreover, a low concentration of ABC294640 sensitized the activity of 5-FU and cisplatin in vitro. In vivo, ABC294640 oral administration dramatically inhibited HT-29 xenografts growth in nude mice.

Conclusions: Targeting of SphK2 by ABC294640 potently inhibits CRC cell growth both in vitro and in vivo, ABC294640 could be developed as a novel therapeutic for the treatment of CRC.

No MeSH data available.


Related in: MedlinePlus

The effect of ABC294640 on SphK activity, S1P or ceramide content in CRC cells. The relative SphK activity (a and b), S1P content (c) or ceramide level (d) (vs. Control group) with indicated ABC294640 treatment were presented. The effect of S1P (5 μM), C6 ceramide (C6, 5 μM) or SKI-II (5 μM) on ABC294640 (1 μM)-induced HT-29 cell growth inhibition and cell death were tested by MTT assay (e) and LDH release assay (f), respectively. Mean values ± SD of three independent experiments were reported. Statistical analysis was performed comparing treatment groups with vehicle control group (“C”). *P < 0.05. #P < 0.05 vs. ABC294640 only group (e and f)
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Fig2: The effect of ABC294640 on SphK activity, S1P or ceramide content in CRC cells. The relative SphK activity (a and b), S1P content (c) or ceramide level (d) (vs. Control group) with indicated ABC294640 treatment were presented. The effect of S1P (5 μM), C6 ceramide (C6, 5 μM) or SKI-II (5 μM) on ABC294640 (1 μM)-induced HT-29 cell growth inhibition and cell death were tested by MTT assay (e) and LDH release assay (f), respectively. Mean values ± SD of three independent experiments were reported. Statistical analysis was performed comparing treatment groups with vehicle control group (“C”). *P < 0.05. #P < 0.05 vs. ABC294640 only group (e and f)

Mentions: Next, we tested the SphK activity in ABC294640-treated CRC cells. As shown in Fig. 2a, ABC294640 at tested concentrations remarkably inhibited SphK activity in HT-29 cells. Further, SphK activity was also decreased in ABC294640-treated HCT-116 cells and DLD-1 cells (Fig. 2b). As a consequence, the S1P content was decreased by ABC294640 in HT-29 cells (Fig. 2c), and the cellular ceramide level was increased (Fig. 2d). Note that, the expression level of SphK2 (tested by Western blots) was not affected by above ABC294640 treatment (Data not shown). Significantly, exogenously-added S1P alleviated ABC294640-induced growth inhibition and apoptosis in HT-29 cells (Fig. 2e and f). Conversely, a short-chain ceramide (C6) and the SphK1 inhibitor SKI-II exacerbated ABC294640-induced HT-29 cytotoxicity (Fig. 2e and f). Ceramide (C6) or the SKI-II alone also induced obvious cytotoxicity in HT-29 cells (Fig. 2e and f). These results indicate that ABC294640-induced anti-CRC activity in vitro is accompanied with SphK inactivation, S1P depletion and ceramide accumulation.Fig. 2


Targeting sphingosine kinase 2 (SphK2) by ABC294640 inhibits colorectal cancer cell growth in vitro and in vivo.

Xun C, Chen MB, Qi L, Tie-Ning Z, Peng X, Ning L, Zhi-Xiao C, Li-Wei W - J. Exp. Clin. Cancer Res. (2015)

The effect of ABC294640 on SphK activity, S1P or ceramide content in CRC cells. The relative SphK activity (a and b), S1P content (c) or ceramide level (d) (vs. Control group) with indicated ABC294640 treatment were presented. The effect of S1P (5 μM), C6 ceramide (C6, 5 μM) or SKI-II (5 μM) on ABC294640 (1 μM)-induced HT-29 cell growth inhibition and cell death were tested by MTT assay (e) and LDH release assay (f), respectively. Mean values ± SD of three independent experiments were reported. Statistical analysis was performed comparing treatment groups with vehicle control group (“C”). *P < 0.05. #P < 0.05 vs. ABC294640 only group (e and f)
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4559903&req=5

Fig2: The effect of ABC294640 on SphK activity, S1P or ceramide content in CRC cells. The relative SphK activity (a and b), S1P content (c) or ceramide level (d) (vs. Control group) with indicated ABC294640 treatment were presented. The effect of S1P (5 μM), C6 ceramide (C6, 5 μM) or SKI-II (5 μM) on ABC294640 (1 μM)-induced HT-29 cell growth inhibition and cell death were tested by MTT assay (e) and LDH release assay (f), respectively. Mean values ± SD of three independent experiments were reported. Statistical analysis was performed comparing treatment groups with vehicle control group (“C”). *P < 0.05. #P < 0.05 vs. ABC294640 only group (e and f)
Mentions: Next, we tested the SphK activity in ABC294640-treated CRC cells. As shown in Fig. 2a, ABC294640 at tested concentrations remarkably inhibited SphK activity in HT-29 cells. Further, SphK activity was also decreased in ABC294640-treated HCT-116 cells and DLD-1 cells (Fig. 2b). As a consequence, the S1P content was decreased by ABC294640 in HT-29 cells (Fig. 2c), and the cellular ceramide level was increased (Fig. 2d). Note that, the expression level of SphK2 (tested by Western blots) was not affected by above ABC294640 treatment (Data not shown). Significantly, exogenously-added S1P alleviated ABC294640-induced growth inhibition and apoptosis in HT-29 cells (Fig. 2e and f). Conversely, a short-chain ceramide (C6) and the SphK1 inhibitor SKI-II exacerbated ABC294640-induced HT-29 cytotoxicity (Fig. 2e and f). Ceramide (C6) or the SKI-II alone also induced obvious cytotoxicity in HT-29 cells (Fig. 2e and f). These results indicate that ABC294640-induced anti-CRC activity in vitro is accompanied with SphK inactivation, S1P depletion and ceramide accumulation.Fig. 2

Bottom Line: Moreover, a low concentration of ABC294640 sensitized the activity of 5-FU and cisplatin in vitro.In vivo, ABC294640 oral administration dramatically inhibited HT-29 xenografts growth in nude mice.Targeting of SphK2 by ABC294640 potently inhibits CRC cell growth both in vitro and in vivo, ABC294640 could be developed as a novel therapeutic for the treatment of CRC.

View Article: PubMed Central - PubMed

Affiliation: Department of Oncology, Shanghai General Hospital, Shanghai Jiaotong University, 100 Haining Road, Shanghai, Hongkou District, 200080, China. caixunshanghai2@163.com.

ABSTRACT

Background: Colorectal cancer (CRC) is a major health problem in China and around the world. It is one of the leading causes of cancer-related deaths. Research groups are thus searching for novel and more efficient anti-CRC agents.

Results: Here we demonstrated that ABC294640, a novel SphK2 inhibitor, induced growth inhibition and apoptosis in transformed and primary CRC cells. The SphK activity was remarkably inhibited by ABC294640, accompanied by sphingosine-1-phosphate (S1P) depletion and ceramide incensement in CRC cells. Exogenously-added S1P inhibited ABC294640-induced HT-29 cell lethality. While C6 ceramide and SphK1 inhibitor SKI-II facilitated ABC294640-induced cytotoxicity against HT-29 cells. ABC294640 inhibited AKT-S6K1, but activated JNK signaling in transformed and primary CRC cells. JNK inhibitors (SP600125 and JNKi-II) alleviated ABC294640-induced CRC cell apoptosis. Moreover, a low concentration of ABC294640 sensitized the activity of 5-FU and cisplatin in vitro. In vivo, ABC294640 oral administration dramatically inhibited HT-29 xenografts growth in nude mice.

Conclusions: Targeting of SphK2 by ABC294640 potently inhibits CRC cell growth both in vitro and in vivo, ABC294640 could be developed as a novel therapeutic for the treatment of CRC.

No MeSH data available.


Related in: MedlinePlus