MCL-1 dependency of cisplatin-resistant cancer cells

Michels, Judith; Obrist, Florine; Vitale, Ilio; Lissa, Delphine; Garcia, Pauline; Behnam‐Motlagh, Parviz; Kohno, Kimitoshi; Wu, Gen Sheng; Brenner, Catherine; Castedo, Maria; Kroemer, Guido

doi:10.1016/j.bcp.2014.07.029

Cited by 57 publications

(38 citation statements)

References 45 publications

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“…Subsequent studies of Mcl-1 have classified the protein as a member of the Bcl-2 family of mitochondrial membrane permeability regulators and defined a dual role for Mcl-1 in myeloid cells: regulating both cell survival and differentiation (77,88). It is the prosurvival function of Mcl-1 that appears to drive the development of myeloid leukemias and other cancers (79,(81)(82)(83)(84)(85)89) in addition to contributing to their drug resistance (89)(90)(91). We have shown that HCMV upregulates Mcl-1 in a transient manner, effectively usurping its prosurvival function to promote early survival of HCMV-infected monocytes (49).…”

Section: Discussionmentioning

confidence: 99%

Human Cytomegalovirus Promotes Survival of Infected Monocytes via a Distinct Temporal Regulation of Cellular Bcl-2 Family Proteins

Collins-McMillen

Kim

Nogalski

et al. 2016

J Virol

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Monocytes IMPORTANCEHematogenous dissemination of HCMV via infected monocytes is a crucial component of the viral survival strategy and is required for the establishment of persistent infection and for viral spread to additional hosts. Our system of infected primary human blood monocytes provides us with an opportunity to answer specific questions about viral spread and persistence in in vivo-relevant myeloid cells that cannot be addressed with the more traditionally used replication-permissive cells. Our goal in examining the mechanisms whereby HCMV reprograms infected monocytes to promote viral dissemination is to uncover new targets for therapeutic intervention that would disrupt key viral survival and persistence strategies. Because of this important role in maintaining survival of HCMV-infected monocytes, our new data on the role of Bcl-2 regulation during viral infection represents a promising molecular target for mitigating viral spread and persistence. H uman cytomegalovirus (HCMV) is a ubiquitous host-restricted betaherpesvirus that infects 60 to 90% of the population and persists for the lifetime of the infected individual (1). HCMV infection results in a wide range of pathogenic outcomes dependent upon the age and immune status of the host (2). Infection of immunocompetent hosts is usually asymptomatic or only mildly symptomatic (3, 4); however, it can cause infectious mononucleosis, is a risk factor for the development of cardiovascular disease (5-9), and has been linked to certain types of cancers in otherwise healthy individuals (10-15). In contrast, HCMV infection leads to significant morbidity and mortality in the immunocompromised. HCMV is an important opportunistic pathogen in AIDS patients (16)(17)(18)(19)(20), is a leading infectious cause of complications in transplant recipients (21-28), and causes severe neurological disease in congenitally infected neonates (29)(30)(31)(32)(33)(34).HCMV pathogenesis and disease result from viral spread to multiple organ sites following primary HCMV infection, a process which appears to be a critical step in the viral persistence strategy, as it allows for the establishment of lifelong persistence within the host, as well as for viral shedding and spread to additional hosts (1,35,36). Monocytes are the primary blood-borne targets for HCMV infection and are thought to be centrally involved in the hematogenous dissemination of the virus to target organ systems (37-41). We propose that HCMV reprograms the biology of infected monocytes, creating the ideal cell type to serve as "Trojan horses" to carry HCMV to target host organ sites and then to

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Section: Discussionmentioning

confidence: 99%

Human Cytomegalovirus Promotes Survival of Infected Monocytes via a Distinct Temporal Regulation of Cellular Bcl-2 Family Proteins

Collins-McMillen

Kim

Nogalski

et al. 2016

J Virol

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“…As a proof-of-principle study, we compared the sensitivities of WT and rictor-KO MEFs, which have differential levels of Mcl-l (Fig. 2), to CDDP, a well-known chemotherapeutic drug widely used for treatment of NSCLC and other cancers, in which Mcl-1 expression negatively impacts their responses to CDDP (25,26). We found that rictor-KO MEFs were indeed more sensitive than WT MEFs to CDDP (Fig.…”

Section: Torkinibs Decreasementioning

confidence: 90%

mTOR Complex 2 Stabilizes Mcl-1 Protein by Suppressing Its Glycogen Synthase Kinase 3-Dependent and SCF-FBXW7-Mediated Degradation

Koo

Yue

Deng

et al. 2015

Molecular and Cellular Biology

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T he mammalian target of rapamycin (mTOR) regulates a variety of biological functions essential for the maintenance of cancer cell survival and growth by forming two complexes through direct interaction with different partner proteins: raptor (mTOR complex 1 [mTORC1]) and rictor (mTORC2) (1, 2). mTORC1 is well known to regulate many key cellular processes, including cell growth and metabolism, primarily via regulating cap-dependent protein translation initiation. However, the biological functions of mTORC2, particularly those related to regulation of oncogenesis, and underlying mechanisms have not been fully elucidated. Nonetheless, mTOR signaling has emerged as an attractive cancer therapeutic target (3). The conventional allosteric mTOR inhibitors rapamycin and its analogues (rapalogs) have shown success in the treatment of a few types of cancer (4, 5). In addition, great efforts have also been made to develop novel mTOR kinase inhibitors (TORKinibs) that suppress both mTORC1 and mTORC2 activities. As a result, several ATP-competitive inhibitors of mTOR kinase such as INK128 and AZD8055 have been developed and are being tested in clinical trials (5, 6).Mcl-1 is a well-known Bcl-2 family protein that negatively regulates apoptosis by binding and sequestering proapoptotic proteins such as Bax, Bak, Noxa, and Bim (7). Its expression can be controlled at various levels, including transcription, translation, and posttranslation (7). mTORC1 is known to regulate Mcl-1 translation, which contributes to mTORC1-dependent survival (8). However, it is unknown whether mTORC2 regulates Mcl-1 expression.Mcl-1 is a short-lived protein known to undergo ubiquitination/proteasome-mediated degradation (7). One degradation mechanism involves glycogen synthase kinase 3 (GSK3), which phosphorylates Mcl-1 at Ser159, triggering Mcl-1 degradation (9, 10). Mcl-1 phosphorylation at Ser159 facilitates the association of Mcl-1 with the E3 ligase ␤-transducin repeats-containing protein (␤-TrCP) or F-box/WD repeat-containing protein 7 (FBXW7), resulting in ␤-TrCP-or FBXW7-mediated ubiquitination and degradation of 11,12). Therefore, GSK3 plays a critical role in the negative regulation of Mcl-1 stability.Our recent study has revealed that GSK3 is required for TORKinibs to decrease cyclin D1 levels by enhancing its degradation and to inhibit the growth of cancer cells both in vitro and in vivo (13). Moreover, we have shown that inhibition of mTORC2 is responsible for GSK3-dependent cyclin D1 degradation induced by TORKinibs (13). In this study, we were interested in determining whether, and by which mechanisms, mTORC2 regulates Mcl-1 stability and whether inhibition of mTORC2 triggers GSK3-dependent Mcl-1 degradation. Indeed, we have demonstrated that mTORC2 stabilizes Mcl-1 by directly suppressing GSK3-dependent and FBXW7-mediated protein degradation. MATERIALS AND METHODSReagents. All TORKinibs, the GSK3 inhibitor SB216763, the proteasome inhibitor MG132, and the protein synthesis inhibitor cycloheximide (CHX) were the same as described pre...

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“…This excludes the possibility that the hyperactivation of PARP would directly cause the selective vulnerability of such cells to starvation-induced death. Of note, knockdown of pro-apoptotic proteins from the BCL2 family (BAK, BAX, PUMA) reduced killing of R2 and R4 cells by EBSS, while knockdown of MCL1, which is anti-apoptotic (Kozopas et al, 1993;Michels et al, 2014b), accelerated killing by EBSS ( Fig EV1E and F). These results suggest the involvement of the mitochondrial cell death pathway in starvation-induced cell death of CDDP-resistant cancer cells.…”

Section: Cisplatin-resistant Cancer Cells Are Sensitive To Starvationmentioning

confidence: 94%

Metabolic vulnerability of cisplatin‐resistant cancers

et al. 2018

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Cisplatin is the most widely used chemotherapeutic agent, and resistance of neoplastic cells against this cytoxicant poses a major problem in clinical oncology. Here, we explored potential metabolic vulnerabilities of cisplatin-resistant non-small human cell lung cancer and ovarian cancer cell lines. Cisplatin-resistant clones were more sensitive to killing by nutrient deprivation and than their parental cisplatin-sensitive controls. The susceptibility of cisplatin-resistant cells to starvation could be explained by a particularly strong dependence on glutamine. Glutamine depletion was sufficient to restore cisplatin responses of initially cisplatin-resistant clones, and glutamine supplementation rescued cisplatin-resistant clones from starvation-induced death. Mass spectrometric metabolomics and specific interventions on glutamine metabolism revealed that, in cisplatin-resistant cells, glutamine is mostly required for nucleotide biosynthesis rather than for anaplerotic, bioenergetic or redox reactions. As a result, cisplatin-resistant cancers became exquisitely sensitive to treatment with antimetabolites that target nucleoside metabolism.

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MCL-1 dependency of cisplatin-resistant cancer cells

Cited by 57 publications

References 45 publications

Human Cytomegalovirus Promotes Survival of Infected Monocytes via a Distinct Temporal Regulation of Cellular Bcl-2 Family Proteins

Human Cytomegalovirus Promotes Survival of Infected Monocytes via a Distinct Temporal Regulation of Cellular Bcl-2 Family Proteins

mTOR Complex 2 Stabilizes Mcl-1 Protein by Suppressing Its Glycogen Synthase Kinase 3-Dependent and SCF-FBXW7-Mediated Degradation

Metabolic vulnerability of cisplatin‐resistant cancers

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