Inhibition of phospholipaseD2 increases hypoxia-induced human colon cancer cell apoptosis through inactivating of the PI3K/AKT signaling pathway
- 272 Downloads
Hypoxia is a common feature of solid tumor, and is a direct stress that triggers apoptosis in many human cell types. As one of solid cancer, hypoxia exists in the whole course of colon cancer occurrence and progression. Our previous studies shown that hypoxia induce high expression of phospholipase D2 (PLD2) and survivin in colon cancer cells. However, the correlation between PLD2 and survivin in hypoxic colon cancer cells remains unknown. In this study, we observed significantly elevated PLD2 and survivin expression levels in colon cancer tissues and cells. This is a positive correlation between of them, and co-expression of PLD2 and survivin has a positive correlation with the clinicpatholic features including tumor size, TNM stage, and lymph node metastasis. We also found that hypoxia induced the activity of PLD increased significant mainly caused by PLD2 in colon cancer cells. However, inhibition the activity of PLD2 induced by hypoxia promotes the apoptosis of human colon cancer cells, as well as decreased the expression of apoptosis markers including survivin and bcl2. Moreover, the pharmacological inhibition of PI3K/AKT supported the hypothesis that promotes the apoptosis of hypoxic colon cancer cells by PLD2 activity inhibition may through inactivation of the PI3K/AKT signaling pathway. Furthermore, interference the PLD2 gene expression leaded to the apoptosis of hypoxic colon cancer cells increased and also decreased the expression level of survivin and bcl2 may through inactivation of PI3K/AKT signaling pathway. These results indicated that PLD2 play antiapoptotic role in colon cancer under hypoxic conditions, inhibition of the activity, or interference of PLD2 gene expression will benefit for the treatment of colon cancer patients.
KeywordsPLD2 Apoptosis Hypoxia PI3K/AKT Colon cancer
This work was supported by the National Natural Science Foundation of China, no. 81201916. The authors gratefully thank Laboratory Research Center of the First Affiliated Hospital of Chongqing Medical University for providing equipment support.
Compliance with ethical standards
Conflicts of interest
- 5.Uchida N, Okamura S, Kuwano H. Phospholipase D activity in human gastric carcinoma. Anticancer Res. 1999;19:77–86.Google Scholar
- 15.Yamakawa H, Banno Y, Nakashima S, Sawada M, Yamada J, Yoshimura S, et al. Increased phospholipase D2 activity during hypoxia-induced death of PC12 cells: its possible anti-apoptotic role. Neurol Rep. 2000;16:3647–50.Google Scholar
- 22.Zhang S, Liu B, Zhang B, Fan Z. The effect of survivin expression on the apoptosis and proliferation of hypoxic human pulmonary arterial smooth muscle cells. Zhonghua jiehe he huxi zazi. 2015;38:45–9.Google Scholar
- 24.K.J.Oh, S.C. Lee, H.j. Choi, D.Y.Oh, S.C. Kim, D.S. Min, J.M. Kim, K.S. Lee, J.S. Han. Role of phospholipase D2 in anti-apoptotic signaling through increased expression of Bcl2 and Bcl-xL.J. Cell. Biochem. 2007.Google Scholar
- 34.Thomas P. Mathews, Salisha Hill,Kristie L. Rose,Pavlina T. Ivanova,Craig W. Lindsley and H. Alex Brown, Human phospholipase D activity transiently regulates pyrimidine biosynthesis in malignant gliomas. ACS Chemical Biology. 2015. PMID:25646564.Google Scholar
- 47.Mi Hee P, Bong-Hyun A, Yong-Kil H, Do Sik M. Overexpression of phospholipase D enhances matrix metalloproteinase-2 expression and glioma cell invasion via protein kinase C and protein kinase a/NF-κB/SP1-mdiated signaling pathways. Carcinogenesis. 2009;30:356–65.Google Scholar