Autophagic degradation of epidermal growth factor receptor in gefitinib-resistant lung cancer by celastrol

Xu, Su; Law, Betty Yuen Kwan; Mok, Simon Wing Fai; Leung, Elaine Lai Han; Fan, Xing; Coghi, Paolo; Zeng, Wu; Leung, Chung‐Hang; Ma, Dik‐Lung; Liu, Liang; Wong, Vincent Kam Wai

doi:10.3892/ijo.2016.3644

Cited by 25 publications

(16 citation statements)

References 56 publications

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“…Changes in [Ca 2+ ]c were measured by a fluorescent dye, Fluo-3-AM as previously described [ 42 , 43 ]. A2780s and A2780cp cells were treated with Ssd, cell suspensions were incubated with Fluo-3-AM (5 μM, 37°C, 30 min) and subjected to Fluorescence-activated cell sorting (FACS) analysis (BD Biosciences).…”

Section: Methodsmentioning

confidence: 99%

Saikosaponin-d, a calcium mobilizing agent, sensitizes chemoresistant ovarian cancer cells to cisplatin-induced apoptosis by facilitating mitochondrial fission and G2/M arrest

et al. 2017

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Cisplatin (CDDP) and its derivatives are first line anti-cancer drugs for ovarian cancer (OVCA). However, chemoresistance due to high incidence of p53 mutations leads to poor clinical prognosis. Saikosaponin-d (Ssd), a saponin from a herbal plant extract, has been shown to induce cell death and sensitize chemoresistant cells to chemotherapeutic agents. Here, we demonstrated that Ssd sensitized chemoresistant OVCA cells with either p53-wt, -mutant and -null to CDDP. The action of Ssd appears to be through induction of mitochondrial fragmentation and G2/M arrest. Ssd is mediated via calcium signaling, up-regulation of the mitochondrial fission proteins Dynamin-related protein 1 (Drp1) and optic atrophy 1 (Opa1), and loss in mitochondrial membrane potential (MMP). Moreover, in the presence of CDDP, Ssd also down-regulates protein phosphatase magnesium-dependent 1 D (PPM1D) and increases the phosphorylation of checkpoint protein kinases (Chk) 1, cell division cycle 25c (Cdc25c) and Cyclin dependent kinase 1 (Cdk1). Our findings suggest that Ssd could sensitize OVCA to CDDP independent of the p53 status through multiple signaling pathways. They support the notion that Ssd may be a novel adjuvant for the treatment of chemoresistant OVCA.

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Section: Methodsmentioning

confidence: 99%

Saikosaponin-d, a calcium mobilizing agent, sensitizes chemoresistant ovarian cancer cells to cisplatin-induced apoptosis by facilitating mitochondrial fission and G2/M arrest

et al. 2017

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“…Induction of autophagy triggered the localization of EGFR to mitochondria contributing to cell survival [69]. Autophagic degradation of EGFR was caused by the treatment of cancer cells with the protein kinase CK2 inhibitor CX-4945 [65] or with the herbal plant derivative celastraol [70]. This suggests that the induction of autophagy can limit EGFR survival signaling.…”

Section: Egfr Family Members Regulates Autophagymentioning

confidence: 99%

EGFR Family Members’ Regulation of Autophagy Is at a Crossroads of Cell Survival and Death in Cancer

Henson

Chen

Gibson

2017

Cancers

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The epidermal growth factor receptor (EGFR) signaling pathways are altered in many cancers contributing to increased cell survival. These alterations are caused mainly through increased expression or mutation of EGFR family members EGFR, ErbB2, ErbB3, and ErbB4. These receptors have been successfully targeted for cancer therapy. Specifically, a monoclonal antibody against ErbB2, trastuzumab, and a tyrosine kinase inhibitor against EGFR, gefitinib, have improved the survival of breast and lung cancer patients. Unfortunately, cancer patients frequently become resistant to these inhibitors. This has led to investigating how EGFR can contribute to cell survival and how cancer cells can overcome inhibition of its signaling. Indeed, it is coming into focus that EGFR signaling goes beyond a single signal triggering cell proliferation and survival and is a sensor that regulates the cell’s response to microenvironmental stresses such as hypoxia. It acts as a switch that modulates the ability of cancer cells to survive. Autophagy is a process of self-digestion that is inhibited by EGFR allowing cancer cells to survive under stresses that would normally cause death and become resistant to chemotherapy. Inhibiting EGFR signaling allows autophagy to contribute to cell death. This gives new opportunities to develop novel therapeutic strategies to treat cancers that rely on EGFR signaling networks and autophagy. In this review, we summarize the current understanding of EGFR family member regulation of autophagy in cancer cells and how new therapeutic strategies could be developed to overcome drug resistance.

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“…Inhibition of celastrol-induced autophagic degradation of prevents celastrol-mediated cell death in gefitinib-resistant NSCLCs ( Xu et al, 2016 ). The inhibition of EGFR increases in autophagy resulting in increased cell death under hypoxia ( Chen et al, 2016 ).…”

Section: Discussionmentioning

confidence: 99%

DDX53 Promotes Cancer Stem Cell-Like Properties and Autophagy

Kim

Jeoung

2017

Molecules and Cells

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Although cancer/testis antigen DDX53 confers anti-cancer drug-resistance, the effect of DDX53 on cancer stem cell-like properties and autophagy remains unknown. MDA-MB-231 (CD133+) cells showed higher expression of DDX53, SOX-2, NANOG and MDR1 than MDA-MB-231 (CD133−). DDX53 increased in vitro self-renewal activity of MCF-7 while decreasing expression of DDX53 by siRNA lowered in vitro self-renewal activity of MDA-MB-231. DDX53 showed an interaction with EGFR and binding to the promoter sequences of EGFR. DDX53 induced resistance to anti-cancer drugs in MCF-7 cells while decreased expression of DDX53 by siRNA increased the sensitivity of MDA-MB-231 to anti-cancer drugs. Negative regulators of DDX53, such as miR-200b and miR-217, increased the sensitivity of MDA-MB-231 to anti-cancer drugs. MDA-MB-231 showed higher expression of autophagy marker proteins such as ATG-5, pBeclin1Ser15 and LC-3I/II compared with MCF-7. DDX53 regulated the expression of marker proteins of autophagy in MCF-7 and MDA-MB-231 cells. miR-200b and miR-217 negatively regulated the expression of autophagy marker proteins. Chromatin immunoprecipitation assays showed the direct regulation of ATG-5. The decreased expression of ATG-5 by siRNA increased the sensitivity to anti-cancer drugs in MDA-MB-231 cells. In conclusion, DDX53 promotes stem cell-like properties, autophagy, and confers resistance to anti-cancer drugs in breast cancer cells.

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Autophagic degradation of epidermal growth factor receptor in gefitinib-resistant lung cancer by celastrol

Cited by 25 publications

References 56 publications

Saikosaponin-d, a calcium mobilizing agent, sensitizes chemoresistant ovarian cancer cells to cisplatin-induced apoptosis by facilitating mitochondrial fission and G2/M arrest

Saikosaponin-d, a calcium mobilizing agent, sensitizes chemoresistant ovarian cancer cells to cisplatin-induced apoptosis by facilitating mitochondrial fission and G2/M arrest

EGFR Family Members’ Regulation of Autophagy Is at a Crossroads of Cell Survival and Death in Cancer

DDX53 Promotes Cancer Stem Cell-Like Properties and Autophagy

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