Elevated expression of mcl-1 inhibits apoptosis and predicts poor prognosis in patients with surgically resected non-small cell lung cancer

Wen, Qiuyuan; Zhan, Yuting; Zheng, Hongmei; Zang, Hongjing; Luo, Jianmin; Zhang, Yuting; Wang, Weiyuan; Feng, Juan; Lu, Junmi; Chen, Lingjiao; Fan, Songqing

doi:10.1186/s13000-019-0884-3

Cited by 18 publications

(11 citation statements)

References 32 publications

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“…The amplification and overexpression of Mcl-1 have been reported in several cancer types and correlates with poor prognosis and response to treatments (19,(64)(65)(66)(67). Most Mcl-1 inhibitors in preclinical and clinical development target the BH3 binding domain of antiapoptotic Bcl-2 proteins to activate Bax/ Bak-dependent cell death (68).…”

Section: Discussionmentioning

confidence: 99%

Mcl-1 and Bok transmembrane domains: Unexpected players in the modulation of apoptosis

Lucendo

Sancho

Lolicato

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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The Bcl-2 protein family comprises both pro- and antiapoptotic members that control the permeabilization of the mitochondrial outer membrane, a crucial step in the modulation of apoptosis. Recent research has demonstrated that the carboxyl-terminal transmembrane domain (TMD) of some Bcl-2 protein family members can modulate apoptosis; however, the transmembrane interactome of the antiapoptotic protein Mcl-1 remains largely unexplored. Here, we demonstrate that the Mcl-1 TMD forms homooligomers in the mitochondrial membrane, competes with full-length Mcl-1 protein with regards to its antiapoptotic function, and induces cell death in a Bok-dependent manner. While the Bok TMD oligomers locate preferentially to the endoplasmic reticulum (ER), heterooligomerization between the TMDs of Mcl-1 and Bok predominantly takes place at the mitochondrial membrane. Strikingly, the coexpression of Mcl-1 and Bok TMDs produces an increase in ER mitochondrial-associated membranes, suggesting an active role of Mcl-1 in the induced mitochondrial targeting of Bok. Finally, the introduction of Mcl-1 TMD somatic mutations detected in cancer patients alters the TMD interaction pattern to provide the Mcl-1 protein with enhanced antiapoptotic activity, thereby highlighting the clinical relevance of Mcl-1 TMD interactions.

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Section: Discussionmentioning

confidence: 99%

Mcl-1 and Bok transmembrane domains: Unexpected players in the modulation of apoptosis

Lucendo

Sancho

Lolicato

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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“…The protein levels of Bcl-2 and Mcl-1 in various types of tumor tissues were found to be frequently augmented at a higher ratio than the other anti-apoptotic proteins in the Bcl-2 family [26]. In particular, increased expressions of Bcl-2 and Mcl-1 reflect a poor prognosis for many malignancies, including lung cancer [37][38][39]. Not only is their increased expression critical for oncogenesis and cancer progression, but these proteins are also involved in conferring chemotherapeutic drug resistance [35,[40][41][42][43].…”

Section: Discussionmentioning

confidence: 99%

Structure–Activity Relationships and Molecular Docking Analysis of Mcl-1 Targeting Renieramycin T Analogues in Patient-derived Lung Cancer Cells

Petsri

Yokoya

Tungsukruthai

et al. 2020

Cancers

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Myeloid cell leukemia 1 (Mcl-1) and B-cell lymphoma 2 (Bcl-2) proteins are promising targets for cancer therapy. Here, we investigated the structure–activity relationships (SARs) and performed molecular docking analysis of renieramycin T (RT) and its analogues and identified the critical functional groups of Mcl-1 targeting. RT have a potent anti-cancer activity against several lung cancer cells and drug-resistant primary cancer cells. RT mediated apoptosis through Mcl-1 suppression and it also reduced the level of Bcl-2 in primary cells. For SAR study, five analogues of RT were synthesized and tested for their anti-cancer and Mcl-1- and Bcl-2-targeting effects. Only two of them (TM-(–)-18 and TM-(–)-4a) exerted anti-cancer activities with the loss of Mcl-1 and partly reduced Bcl-2, while the other analogues had no such effects. Specific cyanide and benzene ring parts of RT’s structure were identified to be critical for its Mcl-1-targeting activity. Computational molecular docking indicated that RT, TM-(–)-18, and TM-(–)-4a bound to Mcl-1 with high affinity, whereas TM-(–)-45, a compound with a benzene ring but no cyanide for comparison, showed the lowest binding affinity. As Mcl-1 helps cancer cells evading apoptosis, these data encourage further development of RT compounds as well as the design of novel drugs for treating Mcl-1-driven cancers.

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“…High levels of Mcl-1 have been also reported in hematological malignancies and subsequently in a wide range of solid tumors, including breast, ovarian, prostate, pancreatic and non-small cell lung (NSCLC) carcinoma [61][62][63][64][65][66]. Mcl-1 amplification and overexpression are also frequently associated with poor prognosis and resistance to anticancer drugs [67][68][69][70][71][72].…”

Section: Mcl-1 (Myeloid Leukemia Sequence 1)mentioning

confidence: 99%

Inhibition of Anti-Apoptotic Bcl-2 Proteins in Preclinical and Clinical Studies: Current Overview in Cancer

D’Aguanno

Bufalo

2020

Cells

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The dynamic interplay between pro-death and pro-survival Bcl-2 family proteins is responsible for a cell’s fate. Due to the recognized relevance of this family in cancer progression and response to therapy, different efforts have made in recent years in order to develop small molecules able to target anti-apoptotic proteins such as Bcl-2, Bcl-xL and Mcl-1. The limitations of the first Bcl-2 family targeted drugs, regarding on-target and off-target toxicities, have been overcome with the development of venetoclax (ABT-199), the first BH3 mimetic inhibitor approved by the FDA. The purpose of this review is to discuss the state-of-the-art in the development of drugs targeting Bcl-2 anti-apoptotic proteins and to highlight the potential of their application as single agents or in combination for improving anti-cancer therapy, focusing in particular on solid tumors.

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Elevated expression of mcl-1 inhibits apoptosis and predicts poor prognosis in patients with surgically resected non-small cell lung cancer

Cited by 18 publications

References 32 publications

Mcl-1 and Bok transmembrane domains: Unexpected players in the modulation of apoptosis

Mcl-1 and Bok transmembrane domains: Unexpected players in the modulation of apoptosis

Structure–Activity Relationships and Molecular Docking Analysis of Mcl-1 Targeting Renieramycin T Analogues in Patient-derived Lung Cancer Cells

Inhibition of Anti-Apoptotic Bcl-2 Proteins in Preclinical and Clinical Studies: Current Overview in Cancer

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