iASPP and Chemoresistance in Ovarian Cancers: Effects on Paclitaxel-Mediated Mitotic Catastrophe

Jiang, Li; Siu, Michelle K.Y.; Wong, Oscar Gee‐Wan; Tam, Kai Fai; Lü, Xin; Lam, Eric W.‐F.; Ngan, Hextan Y.S.; Le, Xiao Feng; Wong, Eric T.T.; Monteiro, Lara J.; Chan, Hoi Yan; Cheung, Annie N.Y.

doi:10.1158/1078-0432.ccr-11-0588

Cited by 67 publications

(63 citation statements)

References 39 publications

(39 reference statements)

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“…It is well established that, in cancer, iASPP has an oncogenic function, and in several cancer cell lines its experimental silencing promotes apoptosis (Cai et al, 2012;Jiang et al, 2011;Liu et al, 2009;Liu et al, 2008;Pang et al, 2010;Zhang et al, 2011). However, our data are consistent with a previous report that, in non-transformed cells (primary cultures of lymphocytes and fibroblasts), treatment with iASPPspecific siRNA reduced levels of apoptosis (Laska et al, 2007).…”

Section: Discussionsupporting

confidence: 92%

iASPP is a novel autophagy inhibitor in keratinocytes

Chikh

Sanza

Raimondi

et al. 2014

Journal of Cell Science

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BSTRACTThe protein iASPP (encoded by PPP1R13L) is an evolutionarily conserved p53 inhibitor, the expression of which is often upregulated in human cancers. We have recently shown that iASPP is a crucial regulator of epidermal homeostasis. Here, we report that iASPP also acts as autophagy inhibitor in keratinocytes. Our data show that depletion of iASPP protects keratinocytes from apoptosis by modulating the expression of Noxa (also known as PMAIP1). In our model, iASPP expression can affect the fissionfusion cycle, mass and shape of mitochondria. iASPP-silenced keratinocytes display disorganization of cytosolic compartments and increased metabolic stress caused by deregulation of mTORC1 signaling. Moreover, increased levels of lipidated LC3 protein confirmed the activation of autophagy in iASPP-depleted cells. We have identified a novel mechanism modulating autophagy in keratinocytes that relies upon iASPP expression specifically reducing the interaction of Atg5-Atg12 with Atg16L1, an interaction that is essential for autophagosome formation or maturation. Using organotypic culture, we further explored the link between autophagy and differentiation, and we showed that impairing autophagy affects epidermal terminal differentiation. Our data provide an alternative mechanism to explain how epithelial integrity is maintained against environmental stressors and might also improve the understanding of the etiology of skin diseases that are characterized by defects in differentiation and DNA damage responses.

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Section: Discussionsupporting

confidence: 92%

iASPP is a novel autophagy inhibitor in keratinocytes

Chikh

Sanza

Raimondi

et al. 2014

Journal of Cell Science

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“…Current standard treatment of ovarian cancer, in both early and advanced stages, consists of complete cytoreductive surgery followed by chemotherapy, typically based on platinum and paclitaxel (11). However, the development of chemoresistance presents a major impediment for successful treatment.…”

Section: Discussionmentioning

confidence: 99%

Knockdown of cathepsin L sensitizes ovarian cancer cells to chemotherapy

Zhang

Wei

et al. 2016

Oncology Letters

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Abstract. Ovarian cancer is a leading gynecological malignancy associated with high mortality. The development of acquired drug resistance is the primary cause of chemotherapy failure in the treatment of ovarian cancer. To examine the mechanism underlying paclitaxel resistance in ovarian cancer and attempt to reverse it, the present study induced a TAX-resistant ovarian cancer cell line, SKOV3/TAX. Cathepsin L (CTSL) has been found to be overexpressed in ovarian cancer. The aim of the present study was to investigate the possible involvement of CTSL in the development of TAX resistance in ovarian cancer. CTSL expression was knocked down in SKOV3 ovarian cancer cells and their phenotypic changes were analyzed. The effects of silenced CTSL on the resistant cell line were investigated by proliferation and apoptosis analysis compared with control SKOV3 cells. CTSL was more highly expressed in SKOV3/TAX cells compared with SKOV3 cells. Paclitaxel treatment downregulated the expression of CTSL in SKOV-3 but not in the paclitaxel-resistant SKOV3/TAX cells. CTSL small hairpin RNA (shRNA) knockdown significantly potentiated apoptosis induced by paclitaxel compared with SKOV3/TAX cells transfected with control shRNA, suggesting that CTSL contributes to paclitaxel resistance in ovarian cancer cells and that CTSL silencing can enhance paclitaxel-mediated cell apoptosis. Thus, CTSL should be explored as a candidate of therapeutic target for modulating paclitaxel sensitivity in ovarian cancer. IntroductionOvarian cancer is the leading cause of gynecologic cancer-related mortality worldwide, as the majority of patients present with advanced disease at diagnosis (1). The standard treatment for ovarian cancer is surgical cytoreduction and systemic chemotherapy, typically paclitaxel and platinum (2). Although improvement in median survival has been observed in recent decades, the majority of patients eventually succumb to recurrent, progressive disease due to resistance to chemotherapy (3). A combination of paclitaxel and carboplatin has widely been used as the first-line chemotherapy for patients with ovarian cancer. Paclitaxel acts specifically during the G2-M phase of the cell cycle by inducing abnormal spindles and disruption of microtubule dynamics, thereby blocking cell cycle progression. Despite its initial effectiveness as a cancer therapeutic agent, in the majority cases patients eventually become insensitive to paclitaxel-based chemotherapy and relapse (4). With the increasing emergence of paclitaxel resistance, the identification of suitable biomarkers for predicting chemosensitivity to paclitaxel may be key for improving the therapeutic outcome of patients with ovarian cancer.Cathepsin L (CTSL), a lysosomal endopeptidase expressed in most eukaryotic cells, is a member of the papain-like family of cysteine proteinases (5). CTSL has a major role in antigen processing, tumor invasion and metastasis, bone resorption, and turnover of intracellular and secreted proteins involved in growth regulation (6). Increased CTSL leve...

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“…A correlation between ASPP2 mRNA levels and cellular sensitivity to ultraviolet and X-ray radiation in various cancer cell lines has been described [50]. Overexpression of iASPP was shown to induce cellular resistance to apoptosis induced by chemotherapeutic drugs including cisplatin and paclitaxel [43,51]. In addition, the ASPP deregulation primarily occurs in wild type p53 expressing cells [14,43].…”

Section: Restoring P53 Function By Preventing Iaspp and Mdm2 From Inhmentioning

confidence: 99%

Restoring the tumour suppressive function of p53 as a parallel strategy in melanoma therapy

2014

Self Cite

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a b s t r a c tThe tumour suppressor p53 is a master sensor of stress and it controls the expression of hundreds to thousands of genes with diverse biological functions including cell cycle arrest, apoptosis, and senescence. Consequently p53 is the most mutated gene found in human cancer and p53 mutation rate varies from 5% to 95%. Importantly p53 activity is often inactivated in tumours expressing structurally wild type p53. Thus one of the major challenges in cancer research is to restore the tumour suppressive function of p53. Intensive studies in the past decade have demonstrated that in addition to mutation, p53 activities are largely regulated by cellular factors that control the expression level and/or transcriptional activities of p53. MDM2, MDM4, p14ARF and the ASPP family of proteins are among the most studied regulators of p53. With increased understanding of the complexity of p53 regulation, various p53 reactivating approaches are being developed. This review will focus on the recent understanding of p53 inactivation in melanoma and the approaches to reactivate p53 in preclinical studies. Recent success in the therapeutic targeting of the BRAFV600E oncogenic protein was accompanied with subsequent relapse caused by acquired drug resistance.Restoration of the tumour suppressive function of p53 presents a parallel cancer therapeutic opportunity alongside BRAFV600E inhibition. Thus targeted therapy and concurrent reactivation of p53 may be a fertile ground to achieve synergistic killing of the 50% of cancer cells that express structurally wild type p53.

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iASPP and Chemoresistance in Ovarian Cancers: Effects on Paclitaxel-Mediated Mitotic Catastrophe

Cited by 67 publications

References 39 publications

iASPP is a novel autophagy inhibitor in keratinocytes

iASPP is a novel autophagy inhibitor in keratinocytes

Knockdown of cathepsin L sensitizes ovarian cancer cells to chemotherapy

Restoring the tumour suppressive function of p53 as a parallel strategy in melanoma therapy

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