Palbociclib-induced autophagy and senescence in gastric cancer cells

Valenzuela, Claudio; Várgas, Leandro; Martinez, Valentina; Bravo, Sindy; Brown, Nelson E.

doi:10.1016/j.yexcr.2017.09.031

Cited by 52 publications

(33 citation statements)

References 40 publications

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“…Several groups have shown that CDK4 activity [7–11] can suppress autophagy, which represents another central degradation mechanism delivering cytosolic proteins, aggregates, or organelles to lysosomes [38]. In line with this, we observed an increase of the autophagy marker LC3-II in MCL cell line Mino upon co-treatment of bortezomib with palbociclib or after treatment with palbociclib alone (Fig.…”

Section: Resultssupporting

confidence: 85%

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Cyclin D1-CDK4 activity drives sensitivity to bortezomib in mantle cell lymphoma by blocking autophagy-mediated proteolysis of NOXA

et al. 2018

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BackgroundMantle cell lymphoma (MCL) is an aggressive B-non-Hodgkin lymphoma with generally poor outcome. MCL is characterized by an aberrantly high cyclin D1-driven CDK4 activity. New molecular targeted therapies such as inhibitors of the ubiquitin-proteasome system (UPS) have shown promising results in preclinical studies and MCL patients. Our previous research revealed stabilization of the short-lived pro-apoptotic NOXA as a critical determinant for sensitivity to these inhibitors. It is currently unclear how cyclin D1 overexpression and aberrant CDK4 activity affect NOXA stabilization and treatment efficacy of UPS inhibitors in MCL.MethodsThe effect of cyclin D1-driven CDK4 activity on response of MCL cell lines and primary cells to proteasome inhibitor treatment was investigated using survival assays (Flow cytometry, AnnexinV/PI) and Western blot analysis of NOXA protein. Half-life of NOXA protein was determined by cycloheximide treatment and subsequent Western blot analysis. The role of autophagy was analyzed by LC3-II protein expression and autophagolysosome detection. Furthermore, silencing of autophagy-related genes was performed using siRNA and MCL cells were treated with autophagy inhibitors in combination with proteasome and CDK4 inhibition.ResultsIn this study, we show that proteasome inhibitor-mediated cell death in MCL depends on cyclin D1-driven CDK4 activity. Inhibition of cyclin D1/CDK4 activity significantly reduced proteasome inhibitor-mediated stabilization of NOXA protein, mainly driven by an autophagy-mediated proteolysis. Bortezomib-induced cell death was significantly potentiated by compounds that interfere with autophagosomal function. Combined treatment with bortezomib and autophagy inhibitors enhanced NOXA stability leading to super-induction of NOXA protein. In addition to established autophagy modulators, we identified the fatty acid synthase inhibitor orlistat to be an efficient autophagy inhibitor when used in combination with bortezomib. Accordingly, this combination synergistically induced apoptosis both in MCL cell lines and in patient samples.ConclusionOur data demonstrate that CDK4 activity in MCL is critical for NOXA stabilization upon treatment with UPS inhibitors allowing preferential induction of cell death in cyclin D transformed cells. Under UPS blocked conditions, autophagy appears as the critical regulator of NOXA induction. Therefore, inhibitors of autophagy are promising candidates to increase the activity of proteasome inhibitors in MCL.Electronic supplementary materialThe online version of this article (10.1186/s13045-018-0657-6) contains supplementary material, which is available to authorized users.

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Section: Resultssupporting

confidence: 85%

“…In addition to its role in cell cycle progression, cyclin D1 affects different cellular processes via both CDK4-dependent and CDK4-independent mechanisms [6]. Cyclin D1/CDK4 activity has also been shown to suppress the autophagic degradation machinery [7–11]. …”

Section: Introductionmentioning

confidence: 99%

Cyclin D1-CDK4 activity drives sensitivity to bortezomib in mantle cell lymphoma by blocking autophagy-mediated proteolysis of NOXA

et al. 2018

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“…The program of senescence induced by CDK4/6 inhibitors can be augmented through co-treatment to inhibit other pathways. For example, reduced mTOR signalling can augment entry into senescence induced by CDK4/6 inhibition (Yoshida et al 2016) and autophagy inhibitors in combination with CDK4/6 inhibitors can augment senescence (Karakas et al 2016, Valenzuela et al 2017.…”

Section: Short-term Adaptation To Cdk4/6 Inhibitorsmentioning

confidence: 99%

Overcoming CDK4/6 inhibitor resistance in ER-positive breast cancer

Portman

Alexandrou

Carson

et al. 2019

Endocrine-Related Cancer

107

113

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Three inhibitors of CDK4/6 kinases were recently FDA approved for use in combination with endocrine therapy, and they significantly increase the progression-free survival of patients with advanced estrogen receptor-positive (ER+) breast cancer in the first-line treatment setting. As the new standard of care in some countries, there is the clinical emergence of patients with breast cancer that is both CDK4/6 inhibitor and endocrine therapy resistant. The strategies to combat these cancers with resistance to multiple treatments are not yet defined and represent the next major clinical challenge in ER+ breast cancer. In this review, we discuss how the molecular landscape of endocrine therapy resistance may affect the response to CDK4/6 inhibitors, and how this intersects with biomarkers of intrinsic insensitivity. We identify the handful of pre-clinical models of acquired resistance to CDK4/6 inhibitors and discuss whether the molecular changes in these models are likely to be relevant or modified in the context of endocrine therapy resistance. Finally, we consider the crucial question of how some of these changes are potentially amenable to therapy.

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“…However, the pro-apoptotic protein Bax didn't express higher as we have observed in cervical cancer [13], but gradually lessened on the contrary. It may be persuasive that LEE011 induced more cell autophagy and senescence than apoptosis in MDA-MB-231 [30,40]. Taken together, cell proliferation suppression and cell apoptosis accumulation induced by LEE011 rest partly on inhibiting the CDK4/6-cyclin D-Rb-E2F1 pathway in vitro.…”

Section: Discussionmentioning

confidence: 95%

Ribociclib (LEE011) suppresses cell proliferation and induces apoptosis of MDA-MB-231 by inhibiting CDK4/6-cyclin D-Rb-E2F pathway

Xiong

Wang

et al. 2019

Artificial Cells, Nanomedicine, and Biotechnology

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Triple-negative breast cancer (TNBC) stands for a refractory subtype, which predicts poor prognosis and has no effective therapies yet for improving it. Given the restrictions of traditional treatments, novel therapeutic strategies need excavating to alleviate the intrinsic or acquired resistance. Ribociclib, a selective CDK4/6 inhibitor, has successfully prevented cancers from deteriorating by intervening the CDK4/6-cyclin D-Rb-E2F pathway, especially for estrogen receptor-positive (ER þ) breast cancer. However, there still remains limited accessibility referring to TNBC. Performing experiments on MDA-MB-231 cells, we found that LEE011 could suppress cell proliferation, and this suppression tended to be dose-dependently. Western blotting analysis presented significant decrease with the expression of CDK4/6 after LEE011 treated, and other proteins associated with this axis such as cyclin D1, p-Rb, Rb, E2F1 showed aberrant changes. Moreover, LEE011 induced G 0-G 1 phase cell cycle arrest, promoted cell apoptosis, and reduced cell migration in vitro. In addition, tumor growth was remarkably impeded without obvious side-effects in MDA-MB-231 xenograft models. Our research has identified that LEE011 was not completely invalid for MDA-MB-231. Considering its pivotal status in TNBC, the CDK4/6-cyclin D-Rb-E2F pathway informed us the possibility and practicality of Ribociclib (LEE011) as pharmacological intervention, but challenges warrant further validation in prospective studies.

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Palbociclib-induced autophagy and senescence in gastric cancer cells

Cited by 52 publications

References 40 publications

Cyclin D1-CDK4 activity drives sensitivity to bortezomib in mantle cell lymphoma by blocking autophagy-mediated proteolysis of NOXA

Cyclin D1-CDK4 activity drives sensitivity to bortezomib in mantle cell lymphoma by blocking autophagy-mediated proteolysis of NOXA

Overcoming CDK4/6 inhibitor resistance in ER-positive breast cancer

Ribociclib (LEE011) suppresses cell proliferation and induces apoptosis of MDA-MB-231 by inhibiting CDK4/6-cyclin D-Rb-E2F pathway

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