Skip to main content

Advertisement

Log in

Resveratrol plays dual roles in pancreatic cancer cells

  • Original Article - Cancer Research
  • Published:
Journal of Cancer Research and Clinical Oncology Aims and scope Submit manuscript

Abstract

Purpose

Although the potential anticancer effect of resveratrol (RSV) on pancreatic cancer has been reported, its mechanism was not fully understood. The role of vascular endothelial growth factor B (VEGF-B) in cancer remains controversial. Herein, we aimed to examine whether the anticancer effect of RSV was related to the VEGF-B.

Methods

The effect of RSV on pancreatic cancer cell line (capan-2 cells) was evaluated by CCK-8 assay, Hoechst 33342 staining, and flow cytometry. The mRNA level of VEGF-B was measured by real-time PCR. VEGF-B expression was knockdown by small interfering RNA (siRNA).The protein levels of VEGF-B, glycogen synthase kinase-3 beta (GSK-3β), and Bax were measured by Western blot.

Results

Resveratrol treatment inhibited tumor growth, induced apoptosis, and up-regulated Bax expression in capan-2 cells. The mRNA and protein levels of VEGF-B were up-regulated after RSV treatment. However, VEGF-B siRNA treatment increased the apoptotic rate, and inhibited tumor activator GSK-3β, while Bax expression was not affected. The combination of RSV and VEGF-B siRNA showed significantly higher apoptotic rate in comparison with RSV or VEGF-B siRNA mono-treatment group.

Conclusions

Resveratrol plays dual roles in pancreatic cancer: as a tumor suppressor via the up-regulation of Bax; as a tumor activator via the up-regulation of VEGF-B; and the anticancer effect of RSV is much stronger than the cancer promotion effect. The combination of RSV with pharmacological inhibitor of VEGF-B might, therefore, be a promising modality for clinical pancreatic cancer therapy.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  • Albrecht I, Kopfstein L, Strittmatter K, Schomber T, Falkevall A, Hagberg CE, Lorentz P, Jeltsch M, Alitalo K, Eriksson U (2010) Suppressive effects of vascular endothelial growth factor-B on tumor growth in a mouse model of pancreatic neuroendocrine tumorigenesis. PLoS ONE 5:e14109

    Article  PubMed  PubMed Central  Google Scholar 

  • Bass TM, Weinkove D, Houthoofd K, Gems D, Partridge L (2007) Effects of resveratrol on lifespan in Drosophila melanogaster and Caenorhabditis elegans. Mech Ageing Dev 128:546–552

    Article  CAS  PubMed  Google Scholar 

  • Baur JA, Sinclair DA (2006) Therapeutic potential of resveratrol: the in vivo evidence. Nat Rev Drug Discov 5:493–506

    Article  CAS  PubMed  Google Scholar 

  • Castillo-Pichardo L, Cubano LA, Dharmawardhane S (2013) Dietary grape polyphenol resveratrol increases mammary tumor growth and metastasis in immunocompromised mice. BMC Complement Altern Med 13:6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chen CJ, Fu YC, Yu W, Wang W (2013) SIRT3 protects cardiomyocytes from oxidative stress-mediated cell death by activating NF-κB. Biochem Biophys Res Commun 430:798–803

    Article  CAS  PubMed  Google Scholar 

  • Cho IR, Koh SS, Malilas W, Srisuttee R, Moon J, Choi YW, Horio Y, Oh S, Chung YH (2012) SIRT1 inhibits proliferation of pancreatic cancer cells expressing pancreatic adenocarcinoma up-regulated factor (PAUF), a novel oncogene, by suppression of β-catenin. Biochem Biophys Res Commun 423:270–275

    Article  CAS  PubMed  Google Scholar 

  • Do GM, Kwon EY, Kim HJ, Jeon SM, Ha TY, Park T, Choi MS (2008) Long-term effects of resveratrol supplementation on suppression of atherogenic lesion formation and cholesterol synthesis in apo E-deficient mice. Biochem Biophys Res Commun 374:55–59

    Article  CAS  PubMed  Google Scholar 

  • Doble BW, Woodgett JR (2003) GSK-3: tricks of the trade for a multi-tasking kinase. J Cell Sci 116:1175–1186

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Garcea G, Manson M, Neal C, Pattenden C, Sutton C, Dennison A, Berry D (2007) Glycogen synthase kinase-3 beta; A new target in pancreatic cancer? Curr Cancer Drug Tar 7:209–215

    Article  CAS  Google Scholar 

  • Gunningham SP, Currie MJ, Han C, Robinson BA, Scott PA, Harris AL, Fox SB (2001a) VEGF-B expression in human primary breast cancers is associated with lymph node metastasis but not angiogenesis. J Pathol 193:325–332

    Article  CAS  PubMed  Google Scholar 

  • Gunningham SP, Currie MJ, Han C, Turner K, Scott PA, Robinson BA, Harris AL, Fox SB (2001b) Vascular endothelial growth factor-B and vascular endothelial growth factor-C expression in renal cell carcinomas regulation by the von Hippel-Lindau gene and hypoxia. Cancer Res 61:3206–3211

    CAS  PubMed  Google Scholar 

  • Gupta SC, Kannappan R, Reuter S, Kim JH, Aggarwal BB (2011) Chemosensitization of tumors by resveratrol. Ann NY Acad Sci 1215:150–160

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hagberg CE, Falkevall A, Wang X, Larsson E, Huusko J, Nilsson I et al (2010) Vanwildemeersch, vascular endothelial growth factor B controls endothelial fatty acid uptake. Nature 464:917–921

    Article  CAS  PubMed  Google Scholar 

  • Heinemann V, Boeck S, Hinke A, Labianca R, Louvet C (2008) Meta-analysis of randomized trials: evaluation of benefit from gemcitabine-based combination chemotherapy applied in advanced pancreatic cancer. BMC Cancer 8:82

    Article  PubMed  PubMed Central  Google Scholar 

  • Howitz KT, Bitterman KJ, Cohen HY, Lamming DW, Lavu S, Wood JG et al (2003) Sinclair, Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature 425:191–196

    Article  CAS  PubMed  Google Scholar 

  • Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun MJ (2009) Cancer statistics, 2009. CA Cancer J Clin 59:225–249

    Article  PubMed  Google Scholar 

  • Lamont KT, Somers S, Lacerda L, Opie LH, Lecour S (2011) Is red wine a SAFE sip away from cardioprotection? Mechanisms involved in resveratrol-and melatonin-induced cardioprotection. J Pineal Res 50:374–380

    Article  CAS  PubMed  Google Scholar 

  • Leis H, Segrelles C, Ruiz S, Santos M, Paramio JM (2002) Expression, localization, and activity of glycogen synthase kinase 3β during mouse skin tumorigenesis. Mol Carcinogen 35:180–185

    Article  CAS  Google Scholar 

  • Li X (2010) VEGF-B: a thing of beauty. Cell Res 20:741–744

    Article  PubMed  PubMed Central  Google Scholar 

  • Li X, Lee C, Tang Z, Zhang F, Arjunan P, Li Y, Hou X, Kumar A, Dong L (2009) VEGF-B: a survival, or an angiogenic factor? Cell Adhes Migr 3:322–327

    Article  Google Scholar 

  • Liao PC, Ng LT, Lin LT, Richardson CD, Wang GH, Lin CC (2010) Resveratrol arrests cell cycle and induces apoptosis in human hepatocellular carcinoma Huh-7 cells. J Med Food 13:1415–1423

    Article  CAS  PubMed  Google Scholar 

  • Mai W, Kawakami K, Shakoori A, Kyo S, Miyashita K, Yokoi K, Jin M, Shimasaki T, Motoo Y, Minamoto T (2009) Deregulated GSK3β sustains gastrointestinal cancer cells survival by modulating human telomerase reverse transcriptase and telomerase. Clin Cancer Res 15:6810–6819

    Article  CAS  PubMed  Google Scholar 

  • Mamaghani S, Patel S, Hedley DW (2009) Glycogen synthase kinase-3 inhibition disrupts nuclear factor-kappaB activity in pancreatic cancer, but fails to sensitize to gemcitabine chemotherapy. BMC Cancer 9:132

    Article  PubMed  PubMed Central  Google Scholar 

  • Miki H, Uehara N, Kimura A, Sasaki T, Yuri T, Yoshizawa K, Tsubura A (2012) Resveratrol induces apoptosis via ROS-triggered autophagy in human colon cancer cells. Int J Oncol 40:1020–1028

    CAS  PubMed  PubMed Central  Google Scholar 

  • Mishra R (2010) Glycogen synthase kinase 3 beta: can it be a target for oral cancer. Mol Cancer 9:144

    Article  PubMed  PubMed Central  Google Scholar 

  • Mo W, Xu X, Xu L, Wang F, Ke A, Wang X, Guo C (2011) Resveratrol inhibits proliferation and induces apoptosis through the hedgehog signaling pathway in pancreatic cancer cell. Pancreatology 11:601–609

    Article  CAS  PubMed  Google Scholar 

  • Mylona E, Alexandrou P, Giannopoulou I, Liapis G, Sofia M, Keramopoulos A, Nakopoulou L (2007) The prognostic value of vascular endothelial growth factors (VEGFs)-A and-B and their receptor, VEGFR-1, in invasive breast carcinoma. Gynecol Oncol 104:557–563

    Article  CAS  PubMed  Google Scholar 

  • Nakagawa H, Kiyozuka Y, Uemura Y, Senzaki H, Shikata N, Hioki K, Tsubura A (2001) Resveratrol inhibits human breast cancer cell growth and may mitigate the effect of linoleic acid, a potent breast cancer cell stimulator. J Cancer Res Clin Oncol 127:258–264

    Article  CAS  PubMed  Google Scholar 

  • Olofsson B, Pajusola K, Kaipainen A, Von Euler G, Joukov V, Saksela O et al (1996) Vascular endothelial growth factor B, a novel growth factor for endothelial cells. Proc Natl Acad Sci USA 93:2576–2581

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ougolkov AV, Fernandez-Zapico ME, Savoy DN et al (2005) Glycogen synthase 3beta participates in nuclear factor kappaB-mediated gene transcription and cell survival in pancreatic cancer cells. Cancer Res 65:2076–2081

    Article  CAS  PubMed  Google Scholar 

  • Shakoori A, Ougolkov A, Yu ZW, Zhang B, Modarressi MH, Billadeau DD, Mai M, Takahashi Y, Minamoto T (2005) Deregulated GSK3β activity in colorectal cancer: its association with tumor cell survival and proliferation. Biochem Biophys Res Commun 334:1365–1373

    Article  CAS  PubMed  Google Scholar 

  • Shan Z, Yang G, Xiang W, Pei-Jun W, Bin Z (2014) Effects of resveratrol on oral squamous cell carcinoma (OSCC) cells in vitro. J Cancer Res Clin Oncol. doi:10.1007/s00432-013-1575-1

    Google Scholar 

  • Takaoka M (1940) Of the phenolic substances of white hellebore (Veratrum grandiflorum Loes. fil.). J Fac Sci Hokkaido Imp Univ 3:1–16

    CAS  Google Scholar 

  • Valenzano DR, Terzibasi E, Genade T, Cattaneo A, Domenici L, Cellerino A (2006) Resveratrol prolongs lifespan and retards the onset of age-related markers in a short-lived vertebrate. Curr Biol 16:296–300

    Article  CAS  PubMed  Google Scholar 

  • Wood JG, Rogina B, Lavu S, Howitz K, Helfand SL, Tatar M, Sinclair D (2004) Sirtuin activators mimic caloric restriction and delay ageing in metazoans. Nature 430:686–689

    Article  CAS  PubMed  Google Scholar 

  • Yang L, Cai X, Liu J, Jia Z, Jiao J, Zhang J, Li C, Li J, Tang XD (2013) CpG-ODN attenuates pathological cardiac hypertrophy and heart failure by activation of PI3Kα-Akt signaling. PLoS ONE 8:e62373

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhou HB, Yan Y, Sun YN, Zhu JR (2003) Resveratrol induces apoptosis in human esophageal carcinoma cells. World J Gastroenterol 9:408–411

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhou W, Wang L, Gou SM, Wang TI, Zhang M, Liu T, Wang CY (2012) ShRNA silencing glycogen synthase kinase-3 beta inhibits tumor growth and angiogenesis in pancreatic cancer. Cancer Lett 316:178–186

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgement

This research was supported by the National Natural Science Foundation of China (No. 81201206), the Natural Science Foundation of Tianjin (No. 11JCYBJC10000), the Research Fund for the Doctoral Program of Ministry of Education of China (No. 20120031120058), the National Natural Science Foundation of China (No. 81101222), and Science Foundation of Tianjin Medical University (No. 2010ky16). The authors thank Pro. Yang Wang, Zhiping Xie for providing us instruments, and also thank Ms. Nancy Bai for the careful language correction.

Conflict of interest

We declare that we have no conflict of interest.

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Yanna Shen or Zhi Qi.

Additional information

Lei Yang and Liang Yang have contributed equally to this study.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Yang, L., Yang, L., Tian, W. et al. Resveratrol plays dual roles in pancreatic cancer cells. J Cancer Res Clin Oncol 140, 749–755 (2014). https://doi.org/10.1007/s00432-014-1624-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00432-014-1624-4

Keywords

Navigation