Year 2025,
Volume: 6 Issue: 2, 53 - 60, 29.12.2025
Esra Tanrıverdi
,
Vera Avcı
,
Ebru Güçlü
,
Hasibe Vural
References
-
Ahmed M (2020) Colon Cancer: A Clinician’s Perspective in 2019. Gastroenterol Res 13(1):1-10.
-
Axten JM, Medina JR, Feng Y, Shu A, Romeril SP, Grant SW, Li WH, Heerding DA, Minthorn E, Mencken T, Atkins C, Liu Q, Rabindran S, Kumar R, Hong X, Goetz A, Stanley T, Taylor JD, Sigethy SD, Tomberlin GH, Gampe RT (2012) Discovery of 7-methyl-5-(1-{[3-(trifluoromethyl) phenyl] acetyl}-2, 3-dihydro-1 H-indol-5-yl)-7 H-pyrrolo [2, 3-d] pyrimidin-4-amine (GSK2606414), a potent and selective first-in-class inhibitor of protein kinase R (PKR)-like endoplasmic reticulum kinase. J Med Chem 55(16):7193-7207.
-
Axten JM, Romeril SP, Shu A, Ralph J, Medina JR, Feng Y, Li WH, Grant SW, Heerding DA, Minthorn E, Mencken T, Gaul N, Goetz A, Stanley T, Hassell AM, Gampe RT, Atkins C, Kumar R (2013) Discovery of GSK2656157: an optimized PERK inhibitor selected for preclinical development. ACS Med Chem Lett 4(10):964-968.
-
Bhoora S, Punchoo R (2020) Policing cancer: Vitamin d arrests the cell cycle. Int J Mol Sci 21(23):1-20.
-
Bikle DD (2014) Vitamin D Metabolism, Mechanism of Action, and Clinical Applications. Chem Biol 21(3):319-329.
-
Bonsignore G, Martinotti S, Ranzato E (2023) Endoplasmic Reticulum Stress and Cancer: Could Unfolded Protein Response Be a Druggable Target for Cancer Therapy? Int J Mol Sci 24(2):1566.
-
Byers SW, Rowlands T, Beildeck M, Bong YS (2012) Mechanism of action of vitamin D and the vitamin D receptor in colorectal cancer prevention and treatment. Rev Endocr Metab Disord 13(1):31-38.
-
Carlberg C, Muñoz A (2022) An update on vitamin D signaling and cancer. Semin Cancer Biol 79:217-230.
-
Charoenngam N, Holick MF (2020) Immunologic Effects of Vitamin D on Human Health and Disease. Nutrients, 12(7):2097.
-
Cho DH, Jo YK, Kim SC, Park IJ, Kim JC (2012) Down-regulated Expression of ATG5 in Colorectal Cancer. Anticancer Res 32(9):4091.
-
Deng M, Zhang W, Yuan L, Tan J, Chen Z (2020) HIF-1a regulates hypoxia-induced autophagy via translocation of ANKRD37 in colon cancer. Exp Cell Res 95(1):112175.
-
DeVorkin L, Pavey N, Carleton G, Comber A, Ho C, Lim J, McNamara E, Huang H, Kim P, Zacharias LG, Mizushima N, Saitoh T, Akira S, Beckham W, Lorzadeh A, Moksa M, Cao Q, Murthy A, Hirst M, DeBerardinis RJ, Lum JJ (2019) Autophagy regulation of metabolism is required for CD8+ T cell anti-tumor immunity. Cell Rep 27(2):502-513.
-
Díaz GD, Paraskeva C, Thomas MG, Binderup L, Hague A (2000) Apoptosis Is Induced by the Active Metabolite of Vitamin D3 and Its Analogue EB1089 in Colorectal Adenoma and Carcinoma Cells: Possible Implications for Prevention and Therapy. Cancer Res 60(8):2304-2312.
-
Fitzwalter BE, Towers CG, Sullivan KD, Andrysik Z, Hoh M, Ludwig M, O'Prey J, Ryan KM, Espinosa JM, Morgan MJ, Thorburn A (2018) Autophagy Inhibition Mediates Apoptosis Sensitization in Cancer Therapy by Relieving FOXO3a Turnover. Developmental cell 44(5):555–565.
-
Fleet JC, Desmet M, Johnson R, Li Y (2011) Vitamin D and cancer: a review of molecular mechanisms. Biochem J 441(1):61-76.
-
Jamora C, Dennert G, Lee AS (1996) Inhibition of tumor progression by suppression of stress protein GRP78/BiP induction in fibrosarcoma B/C10ME. Proc Natl Acad Sci 93(15):7690-7694.
-
Khriesha A, Bustan Ji Y, Farha RA, Al-Abbasi R, Abu-Irmaileh B (2021) Evaluation of the potential anticancer activity of different vitamin D metabolites on colorectal and breast cancer cell lines. Horm Mol Biol Clin Investig 42(1):3-9.
-
Lee SJ, Kim HP, Jin Y, Choi AMK, Ryter SW (2011) Beclin 1 deficiency is associated with increased hypoxia-induced angiogenesis. Autophagy 7(8):829-839.
-
Muñoz A, Grant WB (2022) Vitamin D and Cancer: An Historical Overview of the Epidemiology and Mechanisms. Nutrients 14(7):1448.
-
Niklaus M, Adams O, Berezowska S, Zlobec I, Graber F, Slotta-Huspenina J, Nitsche U, Rosenberg R, Tschan MP, Langer R (2017) Expression analysis of LC3B and p62 indicates intact activated autophagy is associated with an unfavorable prognosis in colon cancer. Oncotarget 8(33):54604–54615.
-
Pálmer HG, González-Sancho JM, Espada J, Berciano MT, Puig I, Baulida J, Quintanilla M, Cano A, de Herreros AG, Lafarga M, Muñoz A (2001) Vitamin D3 promotes the differentiation of colon carcinoma cells by the induction of E-cadherin and the inhibition of β-catenin signaling. J Cell Biol 154(2):369-388.
-
Pálmer HG, Sánchez-Carbayo M, Ordóñez-Morán P, Larriba MJ, Cordón-Cardó C, Muñoz A (2003) Genetic Signatures of Differentiation Induced by 1α,25-Dihydroxyvitamin D3 in Human Colon Cancer Cells. Cancer Res 63(22):7799-7806.
-
Papamichael D, Audisio RA, Glimelius B, de Gramont A, Glynne-Jones R, Haller D, Köhne CH, Rostoft S, Lemmens V, Mitry E, Rutten H, Sargent D, Sastre J, Seymour M, Starling N, Van Cutsem E, Aapro M (2015) Treatment of colorectal cancer in older patients: International Society of Geriatric Oncology (SIOG) consensus recommendations 2013. Ann Oncol 26(3):463-476.
-
Pike J, Meyer M (2010) The Vitamin D Receptor: New Paradigms for the Regulation of Gene Expression by 1,25-Dihydroxyvitamin D-3, Endocrinol. Metab Clin North Am 39:255-269.
-
Rawla P, Sunkara T, Barsouk A (2019) Epidemiology of colorectal cancer: incidence, mortality, survival, and risk factors. Gastroenterol Rev Gastroenterol 14(2):89-103.
-
Ron D, Walter P (2007) Signal integration in the endoplasmic reticulum unfolded protein response. Nat Rev Mol Cell Biol 8(7):519-529.
-
Sakitani K, Hirata Y, Hikiba Y, Hayakawa Y, Ihara S, Suzuki H, Suzuki N, Serizawa T, Kinoshita H, Sakamoto K, Nakagawa H, Tateishi K, Maeda S, Ikenoue T, Kawazu S, Koike K (2015) Inhibition of autophagy exerts anti-colon cancer effects via apoptosis induced by p53 activation and ER stress. BMC Cancer 15(1):795.
-
Sano R, Reed JC (2013) ER stress-induced cell death mechanisms. Biochim Biophys Acta Mol Cell Res 1833(12):3460-3470.
-
Scherr AL, Jassowicz A, Pató A, Elssner C, Ismail L, Schmitt N, Hoffmeister P, Neukirch L, Gdynia G, Goeppert B, Schulze-Bergkamen H, Jäger D, Köhler BC (2020) Knockdown of Atg7 induces nuclear-LC3 dependent apoptosis and augments chemotherapy in colorectal cancer cells. Int J Mol Sci 21(3):1099.
-
Shi Z, Yu X, Yuan M, Lv W, Feng T, Bai R, Zhong H (2019) Activation of the PERK-ATF4 pathway promotes chemo-resistance in colon cancer cells. Sci Rep 9(1):3210.
-
Shruthi N, Prashanthkumar MV,Venugopalreddy B, Suma MN, Subba Rao VM (2017) Analysis of the Cytotoxic Effects of Vitamin D3 on Colorectal, Breast and Cervical Carcinoma Cell Lines. Biochem Anal Biochem 6(2):2-8.
Siegel RL, Wagle NS, Cercek A, Smith RA, Jemal A (2023) Colorectal cancer statistics, 2023. CA Cancer J Clin 73(3):233-254.
-
Wang G, Lei L, Zhao X, Zhang J, Zhou M, Nan K (2015) Calcitriol inhibits cervical cancer cell proliferation through downregulation of HCCR1 expression. Oncol Res 22(5-6):301-309.
-
White E, DiPaola RS (2009) The Double-Edged Sword of Autophagy Modulation in Cancer. Clin Cancer Res 15(17):5308-5316.
-
Wierzbicka JM, Binek A, Ahrends T, Nowacka JD, Szydłowska A, Turczyk Ł, Wąsiewicz T, Wierzbicki PM, Sądej R, Tuckey RC, Slominski AT, Chybicki J, Adrych K, Kmieć Z, Żmijewski MA (2015) Differential antitumor effects of vitamin D analogues on colorectal carcinoma in culture. Int J Oncol 47(3):1084-1096.
-
Wu X, Hu W, Lu L, Zhao Y, Zhou Y, Xiao Z, Zhang L, Zhang H, Li X, Li W, Wang S, Cho CH, Shen J, Li M (2019) Repurposing vitamin D for treatment of human malignancies via targeting tumor microenvironment. Acta Pharm Sin B 9(2):203-219.
-
Xiao T, Zhu W, Huang W, Lu SS, Li XH, Xiao ZQ, Yi H (2018) RACK1 promotes tumorigenicity of colon cancer by inducing cell autophagy. Cell death & disease 9(12):1148.
Cholecalciferol modulates autophagy and endoplasmic reticulum stress to inhibit colon cancer cell proliferation
Year 2025,
Volume: 6 Issue: 2, 53 - 60, 29.12.2025
Esra Tanrıverdi
,
Vera Avcı
,
Ebru Güçlü
,
Hasibe Vural
Abstract
Cholecalciferol is a type of vitamin D and has significant effects on the human body. Among its many roles, recent studies have shown that cholecalciferol can inhibit the proliferation of various cancer cells. In this study, we aimed to investigate the impact of cholecalciferol treatment on colon cancer cells through endoplasmic reticulum stress and autophagy. First, the cytotoxicity of cholecalciferol was evaluated by XTT. Accordingly, in further analysis cholecalciferol was applied to cells at concentrations of 150 and 250 µM for 48 hours. Colony formation capacity of cells, autophagy and ER-stress associated GRP78/BiP levels were evaluated after cholecalciferol treatment. And, the expression levels of genes linked to autophagy, ER stress, and apoptosis were examined using qRT-PCR. Results show that cholecalciferol suppresses the capacity of colony formation of colon cancer cells while raising ER stress marker GRP78/BiP level and lowering autophagy level. And, it was observed that cholecalciferol decreased the expression level of autophagy-related genes and increased the expression level of ER stress and apoptosis-related genes. These findings suggest that cholecalciferol operates its anticancer effect by suppressing autophagy and enhancing apoptosis through the induction of ER stress in colon cancer cells.
Supporting Institution
Necmettin Erbakan University, Scientific Research Projects
References
-
Ahmed M (2020) Colon Cancer: A Clinician’s Perspective in 2019. Gastroenterol Res 13(1):1-10.
-
Axten JM, Medina JR, Feng Y, Shu A, Romeril SP, Grant SW, Li WH, Heerding DA, Minthorn E, Mencken T, Atkins C, Liu Q, Rabindran S, Kumar R, Hong X, Goetz A, Stanley T, Taylor JD, Sigethy SD, Tomberlin GH, Gampe RT (2012) Discovery of 7-methyl-5-(1-{[3-(trifluoromethyl) phenyl] acetyl}-2, 3-dihydro-1 H-indol-5-yl)-7 H-pyrrolo [2, 3-d] pyrimidin-4-amine (GSK2606414), a potent and selective first-in-class inhibitor of protein kinase R (PKR)-like endoplasmic reticulum kinase. J Med Chem 55(16):7193-7207.
-
Axten JM, Romeril SP, Shu A, Ralph J, Medina JR, Feng Y, Li WH, Grant SW, Heerding DA, Minthorn E, Mencken T, Gaul N, Goetz A, Stanley T, Hassell AM, Gampe RT, Atkins C, Kumar R (2013) Discovery of GSK2656157: an optimized PERK inhibitor selected for preclinical development. ACS Med Chem Lett 4(10):964-968.
-
Bhoora S, Punchoo R (2020) Policing cancer: Vitamin d arrests the cell cycle. Int J Mol Sci 21(23):1-20.
-
Bikle DD (2014) Vitamin D Metabolism, Mechanism of Action, and Clinical Applications. Chem Biol 21(3):319-329.
-
Bonsignore G, Martinotti S, Ranzato E (2023) Endoplasmic Reticulum Stress and Cancer: Could Unfolded Protein Response Be a Druggable Target for Cancer Therapy? Int J Mol Sci 24(2):1566.
-
Byers SW, Rowlands T, Beildeck M, Bong YS (2012) Mechanism of action of vitamin D and the vitamin D receptor in colorectal cancer prevention and treatment. Rev Endocr Metab Disord 13(1):31-38.
-
Carlberg C, Muñoz A (2022) An update on vitamin D signaling and cancer. Semin Cancer Biol 79:217-230.
-
Charoenngam N, Holick MF (2020) Immunologic Effects of Vitamin D on Human Health and Disease. Nutrients, 12(7):2097.
-
Cho DH, Jo YK, Kim SC, Park IJ, Kim JC (2012) Down-regulated Expression of ATG5 in Colorectal Cancer. Anticancer Res 32(9):4091.
-
Deng M, Zhang W, Yuan L, Tan J, Chen Z (2020) HIF-1a regulates hypoxia-induced autophagy via translocation of ANKRD37 in colon cancer. Exp Cell Res 95(1):112175.
-
DeVorkin L, Pavey N, Carleton G, Comber A, Ho C, Lim J, McNamara E, Huang H, Kim P, Zacharias LG, Mizushima N, Saitoh T, Akira S, Beckham W, Lorzadeh A, Moksa M, Cao Q, Murthy A, Hirst M, DeBerardinis RJ, Lum JJ (2019) Autophagy regulation of metabolism is required for CD8+ T cell anti-tumor immunity. Cell Rep 27(2):502-513.
-
Díaz GD, Paraskeva C, Thomas MG, Binderup L, Hague A (2000) Apoptosis Is Induced by the Active Metabolite of Vitamin D3 and Its Analogue EB1089 in Colorectal Adenoma and Carcinoma Cells: Possible Implications for Prevention and Therapy. Cancer Res 60(8):2304-2312.
-
Fitzwalter BE, Towers CG, Sullivan KD, Andrysik Z, Hoh M, Ludwig M, O'Prey J, Ryan KM, Espinosa JM, Morgan MJ, Thorburn A (2018) Autophagy Inhibition Mediates Apoptosis Sensitization in Cancer Therapy by Relieving FOXO3a Turnover. Developmental cell 44(5):555–565.
-
Fleet JC, Desmet M, Johnson R, Li Y (2011) Vitamin D and cancer: a review of molecular mechanisms. Biochem J 441(1):61-76.
-
Jamora C, Dennert G, Lee AS (1996) Inhibition of tumor progression by suppression of stress protein GRP78/BiP induction in fibrosarcoma B/C10ME. Proc Natl Acad Sci 93(15):7690-7694.
-
Khriesha A, Bustan Ji Y, Farha RA, Al-Abbasi R, Abu-Irmaileh B (2021) Evaluation of the potential anticancer activity of different vitamin D metabolites on colorectal and breast cancer cell lines. Horm Mol Biol Clin Investig 42(1):3-9.
-
Lee SJ, Kim HP, Jin Y, Choi AMK, Ryter SW (2011) Beclin 1 deficiency is associated with increased hypoxia-induced angiogenesis. Autophagy 7(8):829-839.
-
Muñoz A, Grant WB (2022) Vitamin D and Cancer: An Historical Overview of the Epidemiology and Mechanisms. Nutrients 14(7):1448.
-
Niklaus M, Adams O, Berezowska S, Zlobec I, Graber F, Slotta-Huspenina J, Nitsche U, Rosenberg R, Tschan MP, Langer R (2017) Expression analysis of LC3B and p62 indicates intact activated autophagy is associated with an unfavorable prognosis in colon cancer. Oncotarget 8(33):54604–54615.
-
Pálmer HG, González-Sancho JM, Espada J, Berciano MT, Puig I, Baulida J, Quintanilla M, Cano A, de Herreros AG, Lafarga M, Muñoz A (2001) Vitamin D3 promotes the differentiation of colon carcinoma cells by the induction of E-cadherin and the inhibition of β-catenin signaling. J Cell Biol 154(2):369-388.
-
Pálmer HG, Sánchez-Carbayo M, Ordóñez-Morán P, Larriba MJ, Cordón-Cardó C, Muñoz A (2003) Genetic Signatures of Differentiation Induced by 1α,25-Dihydroxyvitamin D3 in Human Colon Cancer Cells. Cancer Res 63(22):7799-7806.
-
Papamichael D, Audisio RA, Glimelius B, de Gramont A, Glynne-Jones R, Haller D, Köhne CH, Rostoft S, Lemmens V, Mitry E, Rutten H, Sargent D, Sastre J, Seymour M, Starling N, Van Cutsem E, Aapro M (2015) Treatment of colorectal cancer in older patients: International Society of Geriatric Oncology (SIOG) consensus recommendations 2013. Ann Oncol 26(3):463-476.
-
Pike J, Meyer M (2010) The Vitamin D Receptor: New Paradigms for the Regulation of Gene Expression by 1,25-Dihydroxyvitamin D-3, Endocrinol. Metab Clin North Am 39:255-269.
-
Rawla P, Sunkara T, Barsouk A (2019) Epidemiology of colorectal cancer: incidence, mortality, survival, and risk factors. Gastroenterol Rev Gastroenterol 14(2):89-103.
-
Ron D, Walter P (2007) Signal integration in the endoplasmic reticulum unfolded protein response. Nat Rev Mol Cell Biol 8(7):519-529.
-
Sakitani K, Hirata Y, Hikiba Y, Hayakawa Y, Ihara S, Suzuki H, Suzuki N, Serizawa T, Kinoshita H, Sakamoto K, Nakagawa H, Tateishi K, Maeda S, Ikenoue T, Kawazu S, Koike K (2015) Inhibition of autophagy exerts anti-colon cancer effects via apoptosis induced by p53 activation and ER stress. BMC Cancer 15(1):795.
-
Sano R, Reed JC (2013) ER stress-induced cell death mechanisms. Biochim Biophys Acta Mol Cell Res 1833(12):3460-3470.
-
Scherr AL, Jassowicz A, Pató A, Elssner C, Ismail L, Schmitt N, Hoffmeister P, Neukirch L, Gdynia G, Goeppert B, Schulze-Bergkamen H, Jäger D, Köhler BC (2020) Knockdown of Atg7 induces nuclear-LC3 dependent apoptosis and augments chemotherapy in colorectal cancer cells. Int J Mol Sci 21(3):1099.
-
Shi Z, Yu X, Yuan M, Lv W, Feng T, Bai R, Zhong H (2019) Activation of the PERK-ATF4 pathway promotes chemo-resistance in colon cancer cells. Sci Rep 9(1):3210.
-
Shruthi N, Prashanthkumar MV,Venugopalreddy B, Suma MN, Subba Rao VM (2017) Analysis of the Cytotoxic Effects of Vitamin D3 on Colorectal, Breast and Cervical Carcinoma Cell Lines. Biochem Anal Biochem 6(2):2-8.
Siegel RL, Wagle NS, Cercek A, Smith RA, Jemal A (2023) Colorectal cancer statistics, 2023. CA Cancer J Clin 73(3):233-254.
-
Wang G, Lei L, Zhao X, Zhang J, Zhou M, Nan K (2015) Calcitriol inhibits cervical cancer cell proliferation through downregulation of HCCR1 expression. Oncol Res 22(5-6):301-309.
-
White E, DiPaola RS (2009) The Double-Edged Sword of Autophagy Modulation in Cancer. Clin Cancer Res 15(17):5308-5316.
-
Wierzbicka JM, Binek A, Ahrends T, Nowacka JD, Szydłowska A, Turczyk Ł, Wąsiewicz T, Wierzbicki PM, Sądej R, Tuckey RC, Slominski AT, Chybicki J, Adrych K, Kmieć Z, Żmijewski MA (2015) Differential antitumor effects of vitamin D analogues on colorectal carcinoma in culture. Int J Oncol 47(3):1084-1096.
-
Wu X, Hu W, Lu L, Zhao Y, Zhou Y, Xiao Z, Zhang L, Zhang H, Li X, Li W, Wang S, Cho CH, Shen J, Li M (2019) Repurposing vitamin D for treatment of human malignancies via targeting tumor microenvironment. Acta Pharm Sin B 9(2):203-219.
-
Xiao T, Zhu W, Huang W, Lu SS, Li XH, Xiao ZQ, Yi H (2018) RACK1 promotes tumorigenicity of colon cancer by inducing cell autophagy. Cell death & disease 9(12):1148.