Cryptotanshinone-Induced p53-Dependent Sensitization of Colon Cancer Cells to Apoptotic Drive by Regulation of Calpain and Calcium Homeostasis

Over-expression of calpains in tumor tissues can be associated with cancer progression. Thus, inhibition of calpain activity using specific inhibitors has become a novel approach to control tumor growth. In this study, the anticancer potential of cryptotanshinone in combination with calpain inhibitor had been investigated in colon cancer cells and tumor xenograft. Cryptotanshinone elicited an initial endoplasmic reticular (ER) stress response, whereas prolonged stress would result in the promotion of apoptosis. It was then discovered that cryptotanshinone could cause rapid and sustained increase in cytosolic calcium in colon cancer cells accompanied by early GRP78 overexpression, which could be attenuated by pre-treatment of the calcium chelator BAPTA-AM. Cryptotanshinone also facilitated an early increase in calpain activity, which could be blocked by BAPTA-AM or the calpain inhibitor PD150606. A dynamic interaction between GRP78 and calpain during the action of cryptotanshinone was unveiled. This together with the altered NF-[Formula: see text]B signaling could be abolished by calpain inhibitor. GRP78 knockdown increased the sensitivity of cancer cells to cryptotanshinone-evoked apoptosis and reduction of cancer cell colony formation. Such sensitization of drug action had been confirmed to be p53-dependent by using p53-mutated (HT-29) and p53-deficient (HCT116 p53−∕−) cells. The synergistic antitumor effect of cryptotanshinone and calpain inhibitor was further exhibited in vivo. Taken together, findings in this study exemplify a new chemotherapeutic regimen comprising cryptotanshinone and calpain inhibitor by regulation of calpain and calcium homeostasis. This has provided us with new insights in the search of a potential target-specific neoadjuvant therapy against colon cancer.

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Magnetic Compression of Tumor Spheroids Increases Cell Proliferation In Vitro and Cancer Progression In Vivo

Cancers ◽

10.3390/cancers14020366 ◽

2022 ◽

Vol 14 (2) ◽

pp. 366

Author(s):

Gaëtan Mary ◽

Brice Malgras ◽

Jose Efrain Perez ◽

Irène Nagle ◽

Nathalie Luciani ◽

...

Keyword(s):

Colon Cancer ◽

Cancer Cells ◽

Cancer Progression ◽

Peritoneal Cancer Index ◽

Colon Cancer Cells ◽

Tumor Spheroids ◽

Proliferating Cells ◽

The Impact

A growing tumor is submitted to ever-evolving mechanical stress. Endoscopic procedures add additional constraints. However, the impact of mechanical forces on cancer progression is still debated. Herein, a set of magnetic methods is proposed to form tumor spheroids and to subject them to remote deformation, mimicking stent-imposed compression. Upon application of a permanent magnet, the magnetic tumor spheroids (formed from colon cancer cells or from glioblastoma cells) are compressed by 50% of their initial diameters. Such significant deformation triggers an increase in the spheroid proliferation for both cell lines, correlated with an increase in the number of proliferating cells toward its center and associated with an overexpression of the matrix metalloproteinase−9 (MMP−9). In vivo peritoneal injection of the spheroids made from colon cancer cells confirmed the increased aggressiveness of the compressed spheroids, with almost a doubling of the peritoneal cancer index (PCI), as compared with non-stimulated spheroids. Moreover, liver metastasis of labeled cells was observed only in animals grafted with stimulated spheroids. Altogether, these results demonstrate that a large compression of tumor spheroids enhances cancer proliferation and metastatic process and could have implications in clinical procedures where tumor compression plays a role.

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Faculty Opinions recommendation of DHA induces ER stress and growth arrest in human colon cancer cells: associations with cholesterol and calcium homeostasis.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1115344.571363 ◽

2008 ◽

Author(s):

Kishor M Wasan

Keyword(s):

Colon Cancer ◽

Er Stress ◽

Cancer Cells ◽

Calcium Homeostasis ◽

Growth Arrest ◽

Human Colon ◽

Colon Cancer Cells ◽

Human Colon Cancer ◽

Human Colon Cancer Cells

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The Anticancer Action of a Novel 1,2,4-Triazine Sulfonamide Derivative in Colon Cancer Cells

Molecules ◽

10.3390/molecules26072045 ◽

2021 ◽

Vol 26 (7) ◽

pp. 2045

Author(s):

Agnieszka Gornowicz ◽

Anna Szymanowska ◽

Mariusz Mojzych ◽

Robert Czarnomysy ◽

Krzysztof Bielawski ◽

...

Keyword(s):

Colorectal Cancer ◽

Colon Cancer ◽

Cancer Cells ◽

Cathepsin B ◽

Beclin 1 ◽

Special Role ◽

The Novel ◽

Colon Cancer Cells ◽

Sulfonamide Derivative

Cancer therapy is one of the most important challenges of modern medical and chemical sciences. Among the many methods of combating cancer, chemotherapy plays a special role. Imperfect modern chemotherapy justifies continuing the search for new, more effective, and safe drugs. Sulfonamides are the classic group of chemotherapeutic drugs with a broad spectrum of pharmacological activity. Recent literature reports show that sulfonamide derivatives have anti-tumor activity in vitro and in vivo. The aim of the study was to synthesize a novel 1,2,4-triazine sulfonamide derivative and check its anticancer potential in DLD-1 and HT-29 colon cancer cells. The biological studies included MTT assay, DNA biosynthesis, cell cycle analysis, Annexin V binding assay, ethidium bromide/acridine orange staining, and caspase-8, -9, and -3/7 activity. The concentrations of important molecules (sICAM-1, mTOR, Beclin-1, cathepsin B) involved in the pathogenesis and poor prognosis of colorectal cancer were also evaluated by ELISA. We demonstrated that the novel compound was able to induce apoptosis through intrinsic and extrinsic pathways and was capable of decreasing sICAM-1, mTOR, cathepsin B concentrations, whereas increased Beclin-1 concentration was detected in both colon cancer cell lines. The novel compound represents promising multi-targeted potential in colorectal cancer, but further in vivo examinations are needed to confirm the claim.

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ADCK1 activates the β-catenin/TCF signaling pathway to promote the growth and migration of colon cancer cells

Cell Death and Disease ◽

10.1038/s41419-021-03624-9 ◽

2021 ◽

Vol 12 (4) ◽

Author(s):

Yong Ji ◽

Yiqian Liu ◽

Changchun Sun ◽

Lijiang Yu ◽

Zhao Wang ◽

...

Keyword(s):

Colon Cancer ◽

Cancer Cells ◽

Signaling Pathway ◽

Colony Formation ◽

Activation Mechanism ◽

Colon Cancer Cells ◽

Mechanistic Studies ◽

T Cell Factor ◽

And Migration

AbstractAs a result of mutations in the upstream components of the Wnt/β-catenin signaling pathway, this cascade is abnormally activated in colon cancer. Hence, identifying the activation mechanism of this pathway is an urgent need for the treatment of colon cancer. Here, we found an increase in ADCK1 (AarF domain-containing kinase 1) expression in clinical specimens of colon cancer and animal models. Upregulation of ADCK1 expression promoted the colony formation and infiltration of cancer cells. Downregulation of ADCK1 expression inhibited the colony formation and infiltration of cancer cells, in vivo tumorigenesis, migration, and organoid formation. Molecular mechanistic studies demonstrated that ADCK1 interacted with TCF4 (T-cell factor 4) to activate the β-catenin/TCF signaling pathway. In conclusion, our research revealed the functions of ADCK1 in the development of colon cancer and provided potential therapeutic targets.

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Destruxin B Suppresses Drug-Resistant Colon Tumorigenesis and Stemness Is Associated with the Upregulation of miR-214 and Downregulation of mTOR/β-Catenin Pathway

Cancers ◽

10.3390/cancers10100353 ◽

2018 ◽

Vol 10 (10) ◽

pp. 353 ◽

Cited By ~ 4

Author(s):

Szu-Yuan Wu ◽

Yan-Jiun Huang ◽

Yew-Min Tzeng ◽

Chi-Ying Huang ◽

Michael Hsiao ◽

...

Keyword(s):

Colon Cancer ◽

Cancer Cells ◽

Side Population ◽

Colon Cancer Cells ◽

Cancer Stemness ◽

Colon Cells ◽

Colon Tumorigenesis ◽

Tumor Sphere ◽

Sphere Formation

Background: Drug resistance represents a major challenge for treating patients with colon cancer. Accumulating evidence suggests that Insulin-like growth factor (IGF)-associated signaling promotes colon tumorigenesis and cancer stemness. Therefore, the identification of agents, which can disrupt cancer stemness signaling, may provide improved therapeutic efficacy. Methods: Mimicking the tumor microenvironment, we treated colon cancer cells with exogenous IGF1. The increased stemness of IGF1-cultured cells was determined by ALDH1 activity, side-population, tumor sphere formation assays. Destruxin B (DB) was evaluated for its anti-tumorigenic and stemness properties using cellular viability, colony-formation tests. The mimic and inhibitor of miR-214 were used to treat colon cancer cells to show its functional association to DB treatment. In vivo mouse models were used to evaluate DB’s ability to suppress colon tumor-initiating ability and growth inhibitory function. Results: IGF1-cultured colon cancer cells showed a significant increase in 5-FU resistance and enhanced stemness properties, including an increased percentage of ALDH1+, side-population cells, tumor sphere generation in vitro, and increased tumor initiation in vivo. In support, using public databases showed that increased IGF1 expression was significantly associated with a poorer prognosis in patients with colon cancer. DB, a hexadepsipeptide mycotoxin, was able to suppress colon tumorigenic phenotypes, including colony and sphere formation. The sequential treatment of DB, followed by 5-FU, synergistically inhibited the viability of colon cancer cells. In vivo studies showed that DB suppressed the tumorigenesis by 5-FU resistant colon cells, and in a greater degree when combined with 5-FU. Mechanistically, DB treatment was associated with decreased the mammalian target of rapamycin (mTOR) and β-catenin expression and an increased miR-214 level. Conclusion: We provided evidence of DB as a potential therapeutic agent for overcoming 5-FU resistance induced by IGF1, and suppressing cancer stem-like properties in association with miR-214 regulation. Further investigation is warranted for its translation to clinical application.

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932 Targeting the 19S Proteasomal Subunit, Rpt4, in Colon Cancer Cells Induces Cell Death and Reduces Cellular Proliferation In Vitro and In Vivo

Gastroenterology ◽

10.1016/s0016-5085(13)60596-x ◽

2013 ◽

Vol 144 (5) ◽

pp. S-166-S-167

Author(s):

Karen Boland ◽

Caoimhin Concannon ◽

Niamh McCawley ◽

Elaine W. Kay ◽

Deborah McNamara ◽

...

Keyword(s):

Colon Cancer ◽

Cell Death ◽

Cancer Cells ◽

Cellular Proliferation ◽

Colon Cancer Cells ◽

Proliferation In Vitro

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In Vitro and in Vivo antitumor activity and the mechanism of siphonodictyal B in human colon cancer cells

Cancer Medicine ◽

10.1002/cam4.2409 ◽

2019 ◽

Vol 8 (12) ◽

pp. 5662-5672 ◽

Cited By ~ 3

Author(s):

Sonoko Chikamatsu ◽

Ken Saijo ◽

Hiroo Imai ◽

Koichi Narita ◽

Yoshifumi Kawamura ◽

...

Keyword(s):

Colon Cancer ◽

Antitumor Activity ◽

Cancer Cells ◽

Human Colon ◽

Colon Cancer Cells ◽

Human Colon Cancer ◽

In Vivo Antitumor Activity ◽

Human Colon Cancer Cells

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A novel epigenetic regulation of circFoxp1 on Foxp1 in colon cancer cells

Cell Death and Disease ◽

10.1038/s41419-020-03007-6 ◽

2020 ◽

Vol 11 (9) ◽

Author(s):

Yanwei Luo ◽

Fengxia Liu ◽

Jinqi Ma ◽

Yunfeng Fu ◽

Rong Gui

Keyword(s):

Colon Cancer ◽

Cell Viability ◽

Cancer Cells ◽

Quantitative Polymerase Chain Reaction ◽

Human Colon ◽

Tumor Xenograft ◽

Colon Cancer Cells ◽

Poor Overall Survival ◽

Sw620 Cell

Abstract Foxp1 is a tumor suppressor in colon cancer. However, circFoxp1 derived from Foxp1 is an oncogene. In this study, we aim to investigate the role of circFoxp1 in colon cancer and the regulatory mechanism between circFoxp1 and Foxp1. 78 human colon tumor tissues and the matched paracancerous tissues were collected. Quantitative polymerase chain reaction, immunohistochemistry, quantitative methylation-specific PCR, chromatin immunoprecipitation assay, CCK-8 assay, and Tumor xenograft in nude mice were performed. The expression of circFoxp1 was increased and Foxp1 was reduced in colon cancer tissues, which were associated with a poor overall survival rate of the patients with colon cancer. CircFoxp1 recruited DNMT1 to the promoter of Foxp1, leading to promotor hypermethylation, thereby inhibiting Foxp1 transcription. Interfering circFoxp1 by siRNA in SW620 cells significantly inhibited cell viability, while knockdown Foxp1 expression partially restored SW620 cell viability. In addition, knockdown of circFoxp1 significantly sensitized colon cancer cells to Capecitabine in vitro and vivo through regulating Foxp1. We discovered a novel epigenetic pathway that circFoxp1 regulated Foxp1 in colon cancer cells. CircFoxp1 may regulate DNA methylation and demethylation to coordinate colon cancer cell proliferation and participate in chemotherapy drug responses. Therefore, circFoxp1 may be a potential therapeutic target for colon cancer.

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