Simulated microgravity enhances CDDP-induced apoptosis signal via p53-independent mechanisms in cancer cells

Fukazawa, Takahiro; Tanimoto, Keiji; Shrestha, Looniva; Imura, Takeshi; Takahashi, Shinya; Sueda, Taijiro; Hirohashi, Nobuyuki; Hiyama, Eiso; Yuge, Louis

doi:10.1371/journal.pone.0219363

Cited by 23 publications

(25 citation statements)

References 37 publications

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“…Space research and investigations on cell signaling processes in the growth and development of cells exposed to microgravity (µg) is currently a hot topic in cancer research and regenerative medicine [1][2][3][4][5]. Prostate cancer is the fifth leading cause of cancer mortality in men, with the second highest cancer incidence worldwide.…”

Section: Introductionmentioning

confidence: 99%

Simulated Microgravity Influences VEGF, MAPK, and PAM Signaling in Prostate Cancer Cells

Hybel

Dietrichs

Sahana

et al. 2020

IJMS

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Prostate cancer is one of the leading causes of cancer mortality in men worldwide. An unusual but unique environment for studying tumor cell processes is provided by microgravity, either in space or simulated by ground-based devices like a random positioning machine (RPM). In this study, prostate adenocarcinoma-derived PC-3 cells were cultivated on an RPM for time periods of 3 and 5 days. We investigated the genes associated with the cytoskeleton, focal adhesions, extracellular matrix, growth, survival, angiogenesis, and metastasis. The gene expression of signaling factors of the vascular endothelial growth factor (VEGF), mitogen-activated protein kinase (MAPK), and PI3K/AKT/mTOR (PAM) pathways was investigated using qPCR. We performed immunofluorescence to study the cytoskeleton, histological staining to examine the morphology, and a time-resolved immunofluorometric assay to analyze the cell culture supernatants. When PC-3 cells were exposed to simulated microgravity (s-µg), some cells remained growing as adherent cells (AD), while most cells detached from the cell culture flask bottom and formed multicellular spheroids (MCS). After 3-day RPM exposure, PC-3 cells revealed significant downregulation of the VEGF, SRC1, AKT, MTOR, and COL1A1 gene expression in MCS, whereas FLT1, RAF1, MEK1, ERK1, FAK1, RICTOR, ACTB, TUBB, and TLN1 mRNAs were not significantly changed. ERK2 and TLN1 were elevated in AD, and FLK1, LAMA3, COL4A5, FN1, VCL, CDH1, and NGAL mRNAs were significantly upregulated in AD and MCS after 3 days. After a 5-day culture in s-µg, the PC-3 cells showed significant downregulations of VEGF mRNA in AD and MCS, and FN1, CDH1, and LAMA3 in AD and SCR1 in MCS. In addition, we measured significant upregulations in FLT1, AKT, ERK1, ERK2, LCN2, COL1A1, TUBB, and VCL mRNAs in AD and MCS, and increases in FLK1, FN1, and COL4A5 in MCS as well as LAMB2, CDH1, RAF1, MEK1, SRC1, and MTOR mRNAs in AD. FAK1 and RICTOR were not altered by s-µg. In parallel, the secretion rate of VEGFA and NGAL proteins decreased. Cytoskeletal alterations (F-actin) were visible, as well as a deposition of collagen in the MCS. In conclusion, RPM-exposure of PC-3 cells induced changes in their morphology, cytoskeleton, and extracellular matrix protein synthesis, as well as in their focal adhesion complex and growth behavior. The significant upregulation of genes belonging to the PAM pathway indicated their involvement in the cellular changes occurring in microgravity.

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Section: Introductionmentioning

confidence: 99%

Simulated Microgravity Influences VEGF, MAPK, and PAM Signaling in Prostate Cancer Cells

Hybel

Dietrichs

Sahana

et al. 2020

IJMS

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“…Recently, it was demonstrated that simulated microgravity altered the cytoskeleton and nuclear positioning, leading to enhanced cell apoptosis via suppressing the focal adhesion kinase (FAK)/RhoA-controlled mammalian target of rapamycin complex 1 (mTORC1)/nuclear factor-kappa B (NF-κB) and extracellular signal-regulated kinase1 (ERK1/2) pathways [44]. Elsewhere, microgravity altered cis-diamminedichloride platinum (II) (CDDP) sensitivity through the activation of caspase-3 by a p53-independent mechanism in the hepatoblastoma cell line, HepG2 [20]. Microgravity decreased the levels of mTOR and increased the microtubule-associated protein light chain 3-II/I ratio (LC3), suggesting the activation of autophagy.…”

Section: Discussionmentioning

confidence: 99%

“…Microgravity decreased the levels of mTOR and increased the microtubule-associated protein light chain 3-II/I ratio (LC3), suggesting the activation of autophagy. Disturbed immune function in microgravity could be a consequence of ICAM-1 modulation in the monocyte/macrophage system, which, in turn, could have a strong impact on the cells' interaction with T-lymphocytes and migration [20].…”

Section: Discussionmentioning

confidence: 99%

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Changes in the Surface Expression of Intercellular Adhesion Molecule 3, the Induction of Apoptosis, and the Inhibition of Cell-Cycle Progression of Human Multidrug-Resistant Jurkat/A4 Cells Exposed to a Random Positioning Machine

Sokolovskaya

Korneeva

Zaichenko

et al. 2020

IJMS

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Experiments from flight- and ground-based model systems suggest that unexpected alterations of the human lymphoblastoid cell line Jurkat, as well as effects on cell growth, metabolism, and apoptosis, can occur in altered gravity conditions. Using a desktop random positioning machine (RPM), we investigated the effects of simulated microgravity on Jurkat cells and their multidrug-resistant subline, Jurkat/A4 cells. The viability of Jurkat/A4 cells decreased after simulated microgravity in contrast with the Jurkat cells. At the same time, the viability between the experimental Jurkat cells and control Jurkat cells was not significantly different. Of note, Jurkat cells appeared as less susceptible to apoptosis than their multidrug-resistant clone Jurkat/A4 cells, whereas cell-cycle analysis showed that the percentage of Jurkat/A4 cells in the S-phase was increased after 72 and 96 h of RPM-simulated microgravity relative to their static counterparts. The differences in Jurkat cells at all phases between static and simulated microgravity were not significant. The surface expression of the intercellular adhesion molecule 3 (ICAM-3)—also known as cluster of differentiation (CD)50—protein was changed for Jurkat/A4 cells following exposure to the RPM. Changes in cell morphology were observed in the Jurkat/A4 cells after 96 h of RPM-simulated microgravity. Thus, we concluded that Jurkat/A4 cells are more sensitive to RPM-simulated microgravity as compared with the parental Jurkat cell line. We also suggest that intercellular adhesion molecule 3 may be an important adhesion molecule involved in the induction of leukocyte apoptosis. The Jurkat/A4 cells with an acquired multidrug resistance phenotype could be a useful model for studying the effects of simulated microgravity and testing anticancer drugs.

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“…Inhibition of an anti-apoptotic protein, BCL-2, BNIP3 and induction of the apoptosis-related proteins, p53, PARP and BAX in ML-1 thyroid cancer cells has been demonstrated, through the simulated microgravity condition [7]. Tumor antigen p53 responds to stimulated microgravity by induction of downstream proteins such as p21, MDM2 and BAX, which regulate the cell cycle and apoptosis [8]. Apoptosis of thyroid cancer cell lines ML-1 and ONCO-DG1 increased after 24 h exposure to microgravity [9], whereas apoptosis in MDA-MB-231 breast cancer and SGC-7901 gastric adenocarcinoma cells showed increase after 72 h of exposure [10,11].…”

Section: Effect Of Microgravity On the Functioning Of Cancer Cell: Efmentioning

confidence: 99%

An Out of the World Approach for Cancer Treatment

Dutta¹,

Kolkata²

2020

IJAR

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Cancer is still the major cause of mortality and morbidity around the world. Even with the advancements in medical science the number of patients recovering from the disease is low and furthermore chances of tumor relapse and metastasis complicate the disease further. Present tumor therapies either fail to specifically target cancer cells or are prohibitively costly. Significantly, even after decades of research we still do not clear understand the events which initiate tumor formation and thereafter their unchecked growth into a gigantic tumor mass. Like the formation of the universe following the big bang remains a mystery, the formation of the tumor mass following the generation of a single cancer cell is also elusive. Gravitational force plays a major role in shaping our universe, our lives and even cellular biological processes. Similarly, cancer cells could communicate and sense each other through mechanical forces, which have evolved to work in an environment where there's gravity. This thought has motivated various research works to observe the effect of gravity on cancer cells. This review highlights the effect of gravity on the cancer cells.

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Simulated microgravity enhances CDDP-induced apoptosis signal via p53-independent mechanisms in cancer cells

Cited by 23 publications

References 37 publications

Simulated Microgravity Influences VEGF, MAPK, and PAM Signaling in Prostate Cancer Cells

Simulated Microgravity Influences VEGF, MAPK, and PAM Signaling in Prostate Cancer Cells

Changes in the Surface Expression of Intercellular Adhesion Molecule 3, the Induction of Apoptosis, and the Inhibition of Cell-Cycle Progression of Human Multidrug-Resistant Jurkat/A4 Cells Exposed to a Random Positioning Machine

An Out of the World Approach for Cancer Treatment

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