Induction of Plac8 promotes pro-survival function of autophagy in cadmium-induced prostate carcinogenesis

Kolluru, Venkatesh; Pal, Devendra; John, Axel; Ankem, Murali K.; Freedman, Jonathan H.; Damodaran, Chendil

doi:10.1016/j.canlet.2017.08.023

Cited by 42 publications

(32 citation statements)

References 46 publications

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“…We previously demonstrated the implantation of Cdtransformed RWPE-1 cells; these cells formed tumors in xenograft models 33,34 . Similarly, this study helped show that chronic exposure to Cd resulted in malignant transformation of BPH1 cells.…”

Section: Discussionmentioning

confidence: 99%

“…Similarly, this study helped show that chronic exposure to Cd resulted in malignant transformation of BPH1 cells. We previously showed that defective autophagy was responsible for Cd-induced transformation of RWPE-1 33,35 . Here, ZIC2 and GLI1 is responsible for Cd-inducted transformation in BPH1 cells, and it appears that it is specific to BPH1 cells and not to normal prostate epithelial cells.…”

Section: Discussionmentioning

confidence: 99%

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Chronic exposure to cadmium induces a malignant transformation of benign prostate epithelial cells

et al. 2020

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Epidemiological evidence suggests that cadmium (Cd) is one of the causative factors of prostate cancer, but the effect of Cd on benign prostatic hyperplasia (BPH) remains unclear. This study aimed to determine whether Cd exposure could malignantly transform BPH1 cells and, if so, to dissect the mechanism of action. We deciphered the molecular signaling responsible for BPH1 transformation via RNA-sequencing and determined that Cd induced the expression of zinc finger of the cerebellum 2 (ZIC2) in BPH1 cells. We noted Cd exposure increased ZIC2 expression in the Cdtransformed BPH1 cells that in turn promoted anchorage-independent spheroids and increased expression of stem cell drivers, indicating their role in stem cell renewal. Subsequent silencing of ZIC2 expression in transformed cells inhibited spheroid formation, stem cell marker expression, and tumor growth in nude mice. At the molecular level, ZIC2 interacts with the glioma-associated oncogene family (GLI) zinc finger 1 (GLI1), which activates prosurvival factors (nuclear factor NFκB, B-cell lymphoma-2 (Bcl2), as well as an X-linked inhibitor of apoptosis protein (XIAP)) signaling in Cd-exposed BPH1 cells. Conversely, overexpression of ZIC2 in BPH1 cells caused spheroid formation confirming the oncogenic function of ZIC2. ZIC2 activation and GLI1 signaling induction by Cd exposure in primary BPH cells confirmed the clinical significance of this oncogenic function. Finally, human BPH specimens had increased ZIC2 versus adjacent healthy tissues. Thus, we report direct evidence that Cd exposure induces malignant transformation of BPH via activation of ZIC2 and GLI1 signaling. Oncogenesis 1234567890():,; 1234567890():,; 1234567890():,; 1234567890():,;

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Chronic exposure to cadmium induces a malignant transformation of benign prostate epithelial cells

et al. 2020

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“…Furthermore, we found enhanced autophagy in PLAC8-THP-1 cells. Recent studies demonstrated that PLAC8 is a critical regulator of autophagy in pancreatic cancer cell lines and prostate epithelial cells (48,49). Whereas the mechanisms of action of PLAC8 in autophagy are not clear at present, it was possible that PLAC8 regulates the autophagic machinery by facilitating autophagosome-lysosome fusion.…”

Section: Discussionmentioning

confidence: 99%

Placenta Specific 8 Suppresses IL-18 Production through Regulation of Autophagy and Is Associated with Adult Still Disease

Segawa

Kondo

Nakai

et al. 2018

The Journal of Immunology

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Adult Still disease (ASD) is a systemic disorder of unknown etiology characterized by high spiking fever, rash, and arthritis. The purpose of this study was to identify genes specifically associated with the active phase of the disease. In this study, we have reported that placenta specific 8 (PLAC8) was a newly specific gene involved in ASD. DNA microarray and validation analysis using human monocytes revealed that the expression of PLAC8 was significantly higher in active-ASD patients than in inactive-ASD patients and healthy controls. In ASD, PLAC8 expression level correlated with serum levels of CRP, ferritin, IL-1β, and IL-18. Stimulation of monocytes with LPS results in PLAC8 upregulation. LPS or nigericin stimulation of PLAC8-overexpressing human monocytic cell line (THP-1), but not mock THP-1 cells, was associated with a significant decrease in IL-1β and IL-18 production. PLAC8 overexpression in THP-1 cells was associated with enhanced autophagy and suppression of IL-1β and IL-18 production. Therefore, we found that PLAC8 was upregulated in activated monocytes, as was IL-1β and IL-18. The upregulated PLAC8 acts on the synthesis of inactive precursors of IL-1β and IL-18 and seemed to suppress the production of IL-1β and IL-18 by negative feedback through enhanced autophagy, resulting in the suppression of ASD. The results highlight the role of PLAC8 in the pathogenesis of ASD and suggest its potential suitability as an activity marker and therapeutic target in ASD.

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“…From our two previously published studies, PLAC8 was relatively highly expressed in lung cancer and breast cancer tissues, and contributed to cancer progression [12,13]. A number of studies have demonstrated a role of PLAC8 in in the regulation of autophagy during pancreatic cancer progression and prostate carcinogenesis [14,15].…”

Section: Backgroudmentioning

confidence: 98%

“…The sensitivity changes were explored by using MTS and colony formation assays. We here confirmed that MCF7/ADM PLAC8 silencing group become more sensitive to ADM than the control group ( Figure. PLAC8 modulates ADM resistance and autophagy through p62 participation PLAC8 has been shown to promote autophagosome lysosome fusion by activating pro-survival function of autophagy in pancreatic cancer [14,15]. We then assessed PLAC8 regulation to autophagy in breast cancer cells.…”

Section: Intrinsically and Acquired Adm-resistance In Breast Cancer Cmentioning

confidence: 99%

PLAC8 promotes adriamycin resistance via blocking autophagy in breast cancer

chen¹,

Jia

Mao

et al. 2020

Preprint

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Background Adriamycin (ADM) is currently one of the most effective chemotherapeutic agents in breast cancer treatment. However, growing resistance to ADM can lead to treatment failure and poor outcome. The underlying molecular mechanisms in ADM resistance in breast cancer remains unclear. PLAC8 is reported as a novel highly-conserved protein and functions as an oncogene or tumor suppressor in various tumors. Methods Here, we analyzed the expression profile of PLAC8 in breast cancer tissues and breast cancer cell lines, and explored the correlation of PLAC8 expression levels with patients’ outcomes and ADM response. One ADM resistant MCF-7 breast cancer cell (MCF-7/ADM) and its parental cell was used as in vitro models to identify the underlying mechanism of PLAC8 and ADM resistance. Breast cancer cells were transfected with PLAC8 knockdown and overexpression vectors, and MTT and colony formation assays were performed to test the cell response to ADM. Then, we tested the effect of PLAC8 on autophagy pathway by flow cytometry and immunofluorescence analysis, and the change of main autophagy-correlated factors expressions: LC3 and p62. Next, combining treatment of autophagy inhibitor/inducer and PLAC8 downregulation/upregulation revealed the participation of PLAC8 in autophagy pathway to synergistically regulate ADM resistance in breast cancer. Results Here, higher PLAC8 expression was correlated with poorer outcome and aggressive phenotype in breast cancer, and breast cancer patients with higher PLAC8 expression showed potential ADM resistance. PLAC8 expression level was also significantly elevated in ADM resistant MCF-7 breast cancer cells (MCF-7/ADM), compared to parental MCF-7 cells. In vitro experiments further confirmed that PLAC8 inhibition by siRNA or enforced overexpression by infecting pcDNA3.1(C)-PLAC8 plasmid correspondingly decreased or increased the ADM resistance. Subsequently, we demonstrated that ectopic PLAC8 expression in MCF-7/ADM cell blocked the accumulation of the autophagy-associated protein LC3II, and resulted in cellular accumulation of p62. Rapamycin-triggered autophagy significantly increased cell response to ADM, while the autophagy inhibitor 3-MA enhanced ADM resistance. Actually, 3-MA and PLAC8 could synergistically enhance ADM resistance via blocking the autophagy process. Additionally, the downregulation of p62 by siRNA attenuated the activation of autophagy and PLAC8 expression in breast cancer cells. Conclusion Our findings suggest that PLAC8, through participation of p62, inhibits autophagy and consequently results in ADM resistance in breast cancer. PLAC8/p62/autophagy pathway may act as novel therapeutic targets in breast cancer treatment and has potential clinical application in overcoming ADM resistance.

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Induction of Plac8 promotes pro-survival function of autophagy in cadmium-induced prostate carcinogenesis

Cited by 42 publications

References 46 publications

Chronic exposure to cadmium induces a malignant transformation of benign prostate epithelial cells

Chronic exposure to cadmium induces a malignant transformation of benign prostate epithelial cells

Placenta Specific 8 Suppresses IL-18 Production through Regulation of Autophagy and Is Associated with Adult Still Disease

PLAC8 promotes adriamycin resistance via blocking autophagy in breast cancer

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