Cellular Senescence, Represented by Expression of Caveolin-1, in Cancer-Associated Fibroblasts Promotes Tumor Invasion in Pancreatic Cancer

Yamao, Takanobu; Yamashita, Yo‐ichi; Yamamura, Kensuke; Nakao, Yosuke; Tsukamoto, M; Nakagawa, Shigeki; Okabe, Hidetoshi; Hayashi, Hiromitsu; Imai, Katsunori

doi:10.1245/s10434-019-07266-2

Cited by 35 publications

(35 citation statements)

References 48 publications

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“…Cellular senescence has been thought to be an important barrier to tumor formation. Recent studies have shown that SIPS can promote partial tumor invasion [11].…”

Section: Introductionmentioning

confidence: 99%

Stress induced premature senescence promotes proliferation by activating SENEX and p16INK4a/ Retinoblastoma (Rb) pathway in Diffuse Large B-cell Lymphoma

Wang

et al. 2019

Tjh

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Objective: Cellular senescence has been thought to be an important barrier to tumor formation. Recent studies have shown that stressinduced premature senescence (SIPS) can promote partial tumor invasion, but how SIPS affects diffuse large B-cell lymphoma (DLBCL) remains inconclusive. This study aimed to address that issue. Materials and Methods:The immunophenotype of the LY8 cell line was measured with flow cytometry. SIPS induced by tert-butyl hydroperoxide (tBHP) was detected by senescence β-galactosidase staining. Cell proliferation was analyzed with CCK8 and expression levels of ARHGAP18 (SENEX gene-encoding protein), p16/p21, and Rb/pRb were measured with western blot. LY8 cells were transfected with SENEX-SiRNA/NC and verified by western blot. Results:Our results suggested that the immunophenotype of the LY8 cell line is CD19-, CD20-, and CD10-positive and the immunoglobulin light chain is the kappa type. The cellular senescence model of DLBCL could be successfully induced by 30 µM tBHP. ARHGAP18, p21, p16, and Rb protein levels were significantly increased but the level of pRb expression was decreased in the SIPS group compared with other groups. Meanwhile, the proliferation rate was increased in the SIPS group more than other tBHP groups. Furthermore, the expressions of p21 and p16 were significantly decreased in the SENEX-SiRNA group compared with the negative control group. Conclusion: SIPS formation activates ARHGAP18 and the p16/Rb pathway and promotes DLBCL cell proliferation. Furthermore, SENEX activates the p16 pathway in DLBCL. SIPS promotes proliferation by activating SENEX and the p16/Rb pathway in DLBCL. SENEX-related SIPS may serve as an important target for relapsed/refractory DLBCL therapy. Amaç: Hücresel yaşlanmanın tümör oluşumuna karşı önemli bir engel olduğu düşünülmektedir. Son çalışmalarda stresin tetiklediği erken yaşlanmanın (senesens) (SIPS) kısmi tümör invazyonunu kolaylaştırabileceği gösterilmiş olmakla birlikte SIPS'nin diffüz büyük B hücreli lenfomayı (DBBHL) nasıl etkilediği bilinmemektedir. Çalışmada bu konunun ele alınması amaçlanmıştır. Gereç ve Yöntemler: LY8 hücre dizisinin immünfenotipi akış sitometri ile belirlendi. Tert-butil hidroksiperoksitin (tBHP) oluşturduğu SIPS β-galaktozidaz boyası ile tesbit edildi. Hücre proliferasyonu CCK8 ile analiz edildi ve ARGHAP18 (SENEX genini kodlayan protein), p16/p21 ve pRb ekspresyon seviyeleri western-blot ile ölçüldü. LY8 hücreleri SENEX-SiRNA/NC ile transfekte edilerek western-blot ile gösterildi. Bulgular: Sonuçlarımıza göre LY8 hücre dizisinin immünfenotipi CD19, CD20 ve CD10 pozitiftir ve immünoglobulin hafif zinciri kappadır. DBBHL'de hücresel yaşlanma modeli 30 µM tBHP ile başarılı bir şekilde oluşturulabilir. ARHGAP18, p21,p16 ve Rb protein seviyeleri anlamlı olarak arttı fakat pRb ekspresyon seviyeleri diğer gruplarla karşılaştırıldığında SIPS grubunda azaldı. Bu arada, SIPS grubunda, diğer tBHP grubu ile karşılaştırıldığında proliferasyon hızı daha çok arttı. Ek olarak, p21 ve p16 ekspresyonları SENEX-SiRNA grubunda, nega...

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“…Cellular senescence has been thought to be an important barrier to tumor formation. Recent studies have shown that SIPS can promote partial tumor invasion [11].…”

Section: Introductionmentioning

confidence: 99%

Stress induced premature senescence promotes proliferation by activating SENEX and p16INK4a/ Retinoblastoma (Rb) pathway in Diffuse Large B-cell Lymphoma

Wang

et al. 2019

Tjh

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“…In addition to previously mentioned functions, several studies have found that Cav1 may also be related to stress-induced premature senescence in a biphasic manner. Initially, it appeared that Cav1 can be induced by sub-cytotoxic levels of H 2 O 2 , to accelerate premature senescence and mitochondrial dysfunction [182][183][184][185] ; however, when Cav1 expression is inhibited either in Cav1-null mice, or by using antisense Cav1, premature senescence by H 2 O 2 does not occur. [182,186] Recently, it has also been shown that strong suppression of Cav1 induces premature senescence in a p53-p21-dependent manner.…”

Section: Role Of C Av1 In Cellul Ar S Ene Scen Ce and S K In Ag Eingmentioning

confidence: 99%

The importance of caveolins and caveolae to dermatology: Lessons from the caves and beyond

Egger

Rajabi‐Estarabadi

Williams

et al. 2020

Experimental Dermatology

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Caveolae are flask‐shaped invaginations of the cell membrane rich in cholesterol and sphingomyelin, with caveolin proteins acting as their primary structural components that allow compartmentalization and orchestration of various signalling molecules. In this review, we discuss how pleiotropic functions of caveolin‐1 (Cav1) and its intricate roles in numerous cellular functions including lipid trafficking, signalling, cell migration and proliferation, as well as cellular senescence, infection and inflammation, are integral for normal development and functioning of skin and its appendages. We then examine how disruption of the homeostatic levels of Cav1 can lead to development of various cutaneous pathophysiologies including skin cancers, cutaneous fibroses, psoriasis, alopecia, age‐related changes in skin and aberrant wound healing and propose how levels of Cav1 may have theragnostic value in skin physiology/pathophysiology.

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“…The three types of ROS notably decreased the viability and metabolic activity in all three cancer cell lines, especially at concentrations ≥100 µM. Mechanistically, ROS may act via direct oxidation of intracellular proteins or nucleic acids, which promotes regulated cell death and senescence (37)(38)(39), as well as through ROS/reactive nitrogen species-redox signaling events that drive apoptosis via downstream signaling (40-42).…”

Section: Discussionmentioning

confidence: 99%

Hypochlorous acid selectively promotes toxicity and the expression of danger signals in human abdominal cancer cells

Freund

Miebach

Stope³

et al. 2021

Oncol Rep

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Tumors of the abdominal cavity, such as colorectal, pancreatic and ovarian cancer, frequently metastasize into the peritoneum. Large numbers of metastatic nodules hinder curative surgical resection, necessitating lavage with hyperthermic intraperitoneal chemotherapy (HIPEC). However, HIPEC not only causes severe side effects but also has limited therapeutic efficacy in various instances. At the same time, the age of immunotherapies such as biological agents, checkpoint-inhibitors or immune-cell therapies, increasingly emphasizes the critical role of anticancer immunity in targeting malignancies. The present study investigated the ability of three types of long-lived reactive species (oxidants) to inactivate cancer cells and potentially complement current HIPEC regimens, as well as to increase tumor cell expression of danger signals that stimulate innate immunity. The human abdominal cancer cell lines HT-29, Panc-01 and SK-OV-3 were exposed to different concentrations of hydrogen peroxide (H 2 O 2), hypochlorous acid (HOCl) and peroxynitrite (ONOO-). Metabolic activity was measured, as well as determination of cell death and danger signal expression levels via flow cytometry and detection of intracellular oxidation via high-content microscopy. Oxidation of tumor decreased intracellular levels of the antioxidant glutathione and induced oxidation in mitochondria, accompanied by a decrease in metabolic activity and an increase in regulated cell death. At similar concentrations, HOCl showed the most potent effects. Non-malignant HaCaT keratinocytes were less affected, suggesting the approach to be selective to some extent. Pro-immunogenic danger molecules were investigated by assessing the expression levels of calreticulin (CRT), and heat-shock protein (HSP)70 and HSP90. CRT expression was greatest following HOCl and ONOOtreatment, whereas HOCl and H 2 O 2 resulted in the greatest increase in HSP70 and HSP90 expression levels. These results suggested that HOCl may be a promising agent to complement current HIPEC regimens targeting peritoneal carcinomatosis.

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Cellular Senescence, Represented by Expression of Caveolin-1, in Cancer-Associated Fibroblasts Promotes Tumor Invasion in Pancreatic Cancer

Cited by 35 publications

References 48 publications

Stress induced premature senescence promotes proliferation by activating SENEX and p16INK4a/ Retinoblastoma (Rb) pathway in Diffuse Large B-cell Lymphoma

Stress induced premature senescence promotes proliferation by activating SENEX and p16INK4a/ Retinoblastoma (Rb) pathway in Diffuse Large B-cell Lymphoma

The importance of caveolins and caveolae to dermatology: Lessons from the caves and beyond

Hypochlorous acid selectively promotes toxicity and the expression of danger signals in human abdominal cancer cells

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