Cannabinoids Inhibited Pancreatic Cancer via P-21 Activated Kinase 1 Mediated Pathway
Abstract
:1. Introduction
2. Results
2.1. Cannabinoids Inhibited Proliferation of PC and PSC Cells and the Interaction of PC with PSC
2.2. PAK1 Knockout Reduced the Inhibition by Cannabinoids on Proliferation of PC and PSC Cells
2.3. PAK1 Knockout Blocked the Inhibitory Effect of Cannabinoid Oil on Pancreatic Tumour Growth
2.4. Cannabinoids Decreased the Expressions of PD-L1 by PC and PSC Cells via Down-Regulation of PAK1 Activity
3. Discussion
4. Materials and Methods
4.1. Cell and Reagents
4.2. Cell Proliferation Assay
4.3. Mouse Study
4.4. Western Blot
4.5. Statistical Analysis
Author Contributions
Funding
Conflicts of Interest
Abbreviations
CBD | cannabidiol |
THC | (−)-trans-∆9-tetrahydrocannabinol |
PDA | pancreatic ductal adenocarcinoma |
PC | pancreatic cancer |
PSC | pancreatic stellate cell |
PAK1 | p-21 activated kinase 1 |
TME | tumour microenvironment |
PD-L1 | programmed death-ligand |
References
- Laklai, H.; Miroshnikova, Y.A.; Pickup, M.W.; Collisson, E.A.; Kim, G.E.; Barrett, A.S.; Hill, R.C.; Lakins, J.N.; Schlaepfer, D.D.; Mouw, J.K.; et al. Genotype tunes pancreatic ductal adenocarcinoma tissue tension to induce matricellular fibrosis and tumor progression. Nat. Med. 2016, 22, 497–505. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Feig, C.; Jones, J.O.; Kraman, M.; Wells, R.J.; Deonarine, A.; Chan, D.S.; Connell, C.M.; Roberts, E.W.; Zhao, Q.; Caballero, O.L.; et al. Targeting CXCL12 from FAP-expressing carcinoma-associated fibroblasts synergizes with anti-PD-L1 immunotherapy in pancreatic cancer. Proc. Natl. Acad. Sci. USA 2013, 110, 20212–20217. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Ozdemir, B.C.; Pentcheva-Hoang, T.; Carstens, J.L.; Zheng, X.; Wu, C.C.; Simpson, T.R.; Laklai, H.; Sugimoto, H.; Kahlert, C.; Novitskiy, S.V.; et al. Depletion of carcinoma-associated fibroblasts and fibrosis induces immunosuppression and accelerates pancreas cancer with reduced survival. Cancer Cell 2014, 25, 719–734. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Provenzano, P.P.; Cuevas, C.; Chang, A.E.; Goel, V.K.; Von Hoff, D.D.; Hingorani, S.R. Enzymatic targeting of the stroma ablates physical barriers to treatment of pancreatic ductal adenocarcinoma. Cancer Cell 2012, 21, 418–429. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Vonlaufen, A.; Joshi, S.; Qu, C.; Phillips, P.A.; Xu, Z.; Parker, N.R.; Toi, C.S.; Pirola, R.C.; Wilson, J.S.; Goldstein, D.; et al. Pancreatic stellate cells: Partners in crime with pancreatic cancer cells. Cancer Res. 2008, 68, 2085–2093. [Google Scholar] [CrossRef] [Green Version]
- Vennin, C.; Murphy, K.J.; Morton, J.P.; Cox, T.R.; Pajic, M.; Timpson, P. Reshaping the Tumor Stroma for Treatment of Pancreatic Cancer. Gastroenterology 2018, 154, 820–838. [Google Scholar] [CrossRef] [Green Version]
- Biankin, A.V.; Waddell, N.; Kassahn, K.S.; Gingras, M.C.; Muthuswamy, L.B.; Johns, A.L.; Miller, D.K.; Wilson, P.J.; Patch, A.M.; Wu, J.; et al. Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes. Nature 2012, 491, 399–405. [Google Scholar] [CrossRef]
- Wang, K.; Zhan, Y.; Huynh, N.; Dumesny, C.; Wang, X.; Asadi, K.; Herrmann, D.; Timpson, P.; Yang, Y.; Walsh, K.; et al. Inhibition of PAK1 suppresses pancreatic cancer by stimulation of anti-tumour immunity through down-regulation of PD-L1. Cancer Lett 2020, 472, 8–18. [Google Scholar] [CrossRef]
- Yeo, D.; Phillips, P.; Baldwin, G.S.; He, H.; Nikfarjam, M. Inhibition of group 1 p21-activated kinases suppresses pancreatic stellate cell activation and increases survival of mice with pancreatic cancer. Int. J. Cancer 2017, 140, 2101–2111. [Google Scholar] [CrossRef] [Green Version]
- Javid, F.A.; Phillips, R.M.; Afshinjavid, S.; Verde, R.; Ligresti, A. Cannabinoid pharmacology in cancer research: A new hope for cancer patients? Eur. J. Pharmacol. 2016, 775, 1–14. [Google Scholar] [CrossRef]
- Carracedo, A.; Gironella, M.; Lorente, M.; Garcia, S.; Guzman, M.; Velasco, G.; Iovanna, J.L. Cannabinoids induce apoptosis of pancreatic tumor cells via endoplasmic reticulum stress-related genes. Cancer Res. 2006, 66, 6748–6755. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Ferro, R.; Adamska, A.; Lattanzio, R.; Mavrommati, I.; Edling, C.E.; Arifin, S.A.; Fyffe, C.A.; Sala, G.; Sacchetto, L.; Chiorino, G.; et al. GPR55 signalling promotes proliferation of pancreatic cancer cells and tumour growth in mice, and its inhibition increases effects of gemcitabine. Oncogene 2018, 37, 6368–6382. [Google Scholar] [CrossRef]
- Vecera, L.; Gabrhelik, T.; Prasil, P.; Stourac, P. The role of cannabinoids in the treatment of cancer. Bratisl. Lek. Listy 2020, 121, 79–95. [Google Scholar] [CrossRef]
- Hinz, B.; Ramer, R. Anti-tumour actions of cannabinoids. Br. J. Pharmacol. 2019, 176, 1384–1394. [Google Scholar] [CrossRef] [PubMed]
- Huynh, N.; Liu, K.H.; Baldwin, G.S.; He, H. P21-activated kinase 1 stimulates colon cancer cell growth and migration/invasion via ERK- and AKT-dependent pathways. Biochim. Biophys. Acta 2010, 1803, 1106–1113. [Google Scholar] [CrossRef] [Green Version]
- Sledzinski, P.; Zeyland, J.; Slomski, R.; Nowak, A. The current state and future perspectives of cannabinoids in cancer biology. Cancer Med. 2018, 7, 765–775. [Google Scholar] [CrossRef] [PubMed]
- Pellati, F.; Borgonetti, V.; Brighenti, V.; Biagi, M.; Benvenuti, S.; Corsi, L. Cannabis sativa L. and Nonpsychoactive Cannabinoids: Their Chemistry and Role against Oxidative Stress, Inflammation, and Cancer. Biomed. Res. Int. 2018, 2018, 1691428. [Google Scholar] [CrossRef] [Green Version]
- Lauckner, J.E.; Jensen, J.B.; Chen, H.Y.; Lu, H.C.; Hille, B.; Mackie, K. GPR55 is a cannabinoid receptor that increases intracellular calcium and inhibits M current. Proc. Natl. Acad. Sci. USA 2008, 105, 2699–2704. [Google Scholar] [CrossRef] [Green Version]
- Moreno, E.; Andradas, C.; Medrano, M.; Caffarel, M.M.; Perez-Gomez, E.; Blasco-Benito, S.; Gomez-Canas, M.; Pazos, M.R.; Irving, A.J.; Lluis, C.; et al. Targeting CB2-GPR55 receptor heteromers modulates cancer cell signaling. J. Biol. Chem. 2014, 289, 21960–21972. [Google Scholar] [CrossRef] [Green Version]
- Chan, P.C.; Sills, R.C.; Braun, A.G.; Haseman, J.K.; Bucher, J.R. Toxicity and carcinogenicity of delta 9-tetrahydrocannabinol in Fischer rats and B6C3F1 mice. Fundam. Appl. Toxicol. 1996, 30, 109–117. [Google Scholar] [CrossRef]
- Liu, W.M.; Fowler, D.W.; Dalgleish, A.G. Cannabis-derived substances in cancer therapy--an emerging anti-inflammatory role for the cannabinoids. Curr. Clin. Pharmacol. 2010, 5, 281–287. [Google Scholar] [CrossRef] [Green Version]
- Haustein, M.; Ramer, R.; Linnebacher, M.; Manda, K.; Hinz, B. Cannabinoids increase lung cancer cell lysis by lymphokine-activated killer cells via upregulation of ICAM-1. Biochem. Pharmacol. 2014, 92, 312–325. [Google Scholar] [CrossRef]
- Glodde, N.; Jakobs, M.; Bald, T.; Tuting, T.; Gaffal, E. Differential role of cannabinoids in the pathogenesis of skin cancer. Life Sci. 2015, 138, 35–40. [Google Scholar] [CrossRef] [PubMed]
- Ivanov, V.N.; Wu, J.; Wang, T.J.C.; Hei, T.K. Inhibition of ATM kinase upregulates levels of cell death induced by cannabidiol and gamma-irradiation in human glioblastoma cells. Oncotarget 2019, 10, 825–846. [Google Scholar] [CrossRef]
- Topalian, S.L.; Hodi, F.S.; Brahmer, J.R.; Gettinger, S.N.; Smith, D.C.; McDermott, D.F.; Powderly, J.D.; Carvajal, R.D.; Sosman, J.A.; Atkins, M.B.; et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N. Engl. J. Med. 2012, 366, 2443–2454. [Google Scholar] [CrossRef]
- Brahmer, J.R.; Tykodi, S.S.; Chow, L.Q.; Hwu, W.J.; Topalian, S.L.; Hwu, P.; Drake, C.G.; Camacho, L.H.; Kauh, J.; Odunsi, K.; et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N. Engl. J. Med. 2012, 366, 2455–2465. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Emens, L.A.; Ascierto, P.A.; Darcy, P.K.; Demaria, S.; Eggermont, A.M.M.; Redmond, W.L.; Seliger, B.; Marincola, F.M. Cancer immunotherapy: Opportunities and challenges in the rapidly evolving clinical landscape. Eur. J. Cancer 2017, 81, 116–129. [Google Scholar] [CrossRef] [PubMed]
- Myint, Z.W.; Goel, G. Role of modern immunotherapy in gastrointestinal malignancies: A review of current clinical progress. J. Hematol. Oncol. 2017, 10, 86. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Apte, M.V.; Wilson, J.S. Stellate cell activation in alcoholic pancreatitis. Pancreas 2003, 27, 316–320. [Google Scholar] [CrossRef]
- Apte, M.V.; Park, S.; Phillips, P.A.; Santucci, N.; Goldstein, D.; Kumar, R.K.; Ramm, G.A.; Buchler, M.; Friess, H.; McCarroll, J.A.; et al. Desmoplastic reaction in pancreatic cancer: Role of pancreatic stellate cells. Pancreas 2004, 29, 179–187. [Google Scholar] [CrossRef] [Green Version]
- Haber, P.S.; Keogh, G.W.; Apte, M.V.; Moran, C.S.; Stewart, N.L.; Crawford, D.H.; Pirola, R.C.; McCaughan, G.W.; Ramm, G.A.; Wilson, J.S. Activation of pancreatic stellate cells in human and experimental pancreatic fibrosis. Am. J. Pathol. 1999, 155, 1087–1095. [Google Scholar] [CrossRef] [Green Version]
- Olive, K.P.; Jacobetz, M.A.; Davidson, C.J.; Gopinathan, A.; McIntyre, D.; Honess, D.; Madhu, B.; Goldgraben, M.A.; Caldwell, M.E.; Allard, D.; et al. Inhibition of Hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer. Science 2009, 324, 1457–1461. [Google Scholar] [CrossRef] [PubMed] [Green Version]
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Yang, Y.; Huynh, N.; Dumesny, C.; Wang, K.; He, H.; Nikfarjam, M. Cannabinoids Inhibited Pancreatic Cancer via P-21 Activated Kinase 1 Mediated Pathway. Int. J. Mol. Sci. 2020, 21, 8035. https://doi.org/10.3390/ijms21218035
Yang Y, Huynh N, Dumesny C, Wang K, He H, Nikfarjam M. Cannabinoids Inhibited Pancreatic Cancer via P-21 Activated Kinase 1 Mediated Pathway. International Journal of Molecular Sciences. 2020; 21(21):8035. https://doi.org/10.3390/ijms21218035
Chicago/Turabian StyleYang, Yang, Nhi Huynh, Chelsea Dumesny, Kai Wang, Hong He, and Mehrdad Nikfarjam. 2020. "Cannabinoids Inhibited Pancreatic Cancer via P-21 Activated Kinase 1 Mediated Pathway" International Journal of Molecular Sciences 21, no. 21: 8035. https://doi.org/10.3390/ijms21218035