Inhibition of Polyamine Biosynthesis Reverses Ca2+ Channel Remodeling in Colon Cancer Cells

被引:17
作者
Gutierrez, Lucia G. [1 ]
Hernandez-Morales, Miriam [2 ,3 ,4 ]
Nunez, Lucia [1 ]
Villalobos, Carlos [2 ]
机构
[1] Univ Valladolid, IBGM, Valladolid 47003, Spain
[2] CSIC, IBGM, Valladolid 47003, Spain
[3] Univ Calif Berkeley, Dept Elect Engn & Comp Sci, Berkeley, CA 94720 USA
[4] Univ Calif Berkeley, Helen Wills Neurosci Inst, Berkeley, CA 94720 USA
关键词
colorectal cancer; DFMO; store-operated Ca2+ entry; store-operated currents; polyamines; TRPC1; sulindac; INTESTINAL EPITHELIAL RESTITUTION; CALCIUM; TRPC1; PREVENTION; HALLMARKS; SULINDAC; ENTRY; STIM; ORAI;
D O I
10.3390/cancers11010083
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Store-operated Ca2+ entry (SOCE) is the most important Ca2+ entry pathway in non-excitable cells. Colorectal cancer (CRC) shows decreased Ca2+ store content and enhanced SOCE that correlate with cancer hallmarks and are associated to remodeling of store-operated channels (SOCs). Normal colonic cells display small, Ca2+-selective currents driven by Orai1 channels. In contrast, CRC cells display larger, non-selective currents driven by Orai1 and transient receptor potential canonical type 1 channels (TRPC1). Difluoromethylornithine (DFMO), a suicide inhibitor of ornithine decarboxylase (ODC), the limiting step in polyamine biosynthesis, strongly prevents CRC, particularly when combined with sulindac. We asked whether DFMO may reverse SOC remodeling in CRC. We found that CRC cells overexpress ODC and treatment with DFMO decreases cancer hallmarks including enhanced cell proliferation and apoptosis resistance. Consistently, DFMO enhances Ca2+ store content and decreases SOCE in CRC cells. Moreover, DFMO abolish selectively the TRPC1-dependent component of SOCs characteristic of CRC cells and this effect is reversed by the polyamine putrescine. Combination of DFMO and sulindac inhibit both SOC components and abolish SOCE in CRC cells. Finally, DFMO treatment inhibits expression of TRPC1 and stromal interaction protein 1 (STIM1) in CRC cells. These results suggest that polyamines contribute to Ca2+ channel remodeling in CRC, and DFMO may prevent CRC by reversing channel remodeling.
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页数:17
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共 31 条
[1]   Global trends in colorectal cancer mortality: projections to the year 2035 [J].
Araghi, Marzieh ;
Soerjomataram, Isabelle ;
Jenkins, Mark ;
Brierley, James ;
Morris, Eva ;
Bray, Freddie ;
Arnold, Melina .
INTERNATIONAL JOURNAL OF CANCER, 2019, 144 (12) :2992-3000
[2]   Polyamine synthesis as a target of MYC oncogenes [J].
Bachmann, Andre S. ;
Geerts, Dirk .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2018, 293 (48) :18757-18769
[3]   Efficacy and safety of eflornithine (CPP-1X)/sulindac combination therapy versus each as monotherapy in patients with familial adenomatous polyposis (FAP): design and rationale of a randomized, double-blind, Phase III trial [J].
Burke, Carol A. ;
Dekker, Evelien ;
Samadder, N. Jewel ;
Stoffel, Elena ;
Cohen, Alfred .
BMC GASTROENTEROLOGY, 2016, 16
[4]   RhoA enhances store-operated Ca2+ entry and intestinal epithelial restitution by interacting with TRPC1 after wounding [J].
Chung, Hee Kyoung ;
Rathor, Navneeta ;
Wang, Shelley R. ;
Wang, Jian-Ying ;
Rao, Jaladanki N. .
AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY, 2015, 309 (09) :G759-G767
[5]   Aspirin in the Treatment of Cancer: Reductions in Metastatic Spread and in Mortality: A Systematic Review and Meta-Analyses of Published Studies [J].
Elwood, Peter C. ;
Morgan, Gareth ;
Pickering, Janet E. ;
Galante, Julieta ;
Weightman, Alison L. ;
Morris, Delyth ;
Kelson, Mark ;
Dolwani, Sunil .
PLOS ONE, 2016, 11 (04)
[6]   Cancer pharmacoprevention: Targeting polyamine metabolism to manage risk factors for colon cancer [J].
Gerner, Eugene W. ;
Bruckheimer, Elizabeth ;
Cohen, Alfred .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2018, 293 (48) :18770-18778
[7]   Mitochondria sustain store-operated currents in colon cancer cells but not in normal colonic cells: reversal by non-steroidal anti-inflammatory drugs [J].
Hernandez-Morales, Miriam ;
Sobradillo, Diego ;
Valero, Ruth A. ;
Munoz, Eva ;
Ubierna, Daniel ;
Moyer, Mary P. ;
Nunez, Lucia ;
Villalobos, Carlos .
ONCOTARGET, 2017, 8 (33) :55332-55352
[8]   DEPLETION OF INTRACELLULAR CALCIUM STORES ACTIVATES A CALCIUM CURRENT IN MAST-CELLS [J].
HOTH, M ;
PENNER, R .
NATURE, 1992, 355 (6358) :353-356
[9]   CATALYTIC IRREVERSIBLE INHIBITION OF MAMMALIAN ORNITHINE DECARBOXYLASE (E C 4 1 1 17) BY SUBSTRATE AND PRODUCT ANALOGS [J].
METCALF, BW ;
BEY, P ;
DANZIN, C ;
JUNG, MJ ;
CASARA, P ;
VEVERT, JP .
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 1978, 100 (08) :2551-2553
[10]   Difluoromethylornithine Plus Sulindac for the Prevention of Sporadic Colorectal Adenomas: A Randomized Placebo-Controlled, Double-Blind Trial [J].
Meyskens, Frank L., Jr. ;
McLaren, Christine E. ;
Pelot, Daniel ;
Fujikawa-Brooks, Sharon ;
Carpenter, Philip M. ;
Hawk, Ernest ;
Kelloff, Gary ;
Lawson, Michael J. ;
Kidao, Jayashri ;
McCracken, John ;
Albers, C. Gregory ;
Ahnen, Dennis J. ;
Turgeon, D. Kim ;
Goldschmid, Steven ;
Lance, Peter ;
Hagedorn, Curt H. ;
Gillen, Daniel L. ;
Gerner, Eugene W. .
CANCER PREVENTION RESEARCH, 2008, 1 (01) :32-38