Crizotinib (PF-2341066) induces apoptosis due to downregulation of pSTAT3 and BCL-2 family proteins in NPM-ALK+ anaplastic large cell lymphoma

Hamedani, Farid Saei; Cinar, Munevver; Mo, Zhicheng; Cervania, Melissa; Amin, Hesham M.; Alkan, Serhan

doi:10.1016/j.leukres.2013.12.027

Cited by 23 publications

(15 citation statements)

References 26 publications

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“…Nevertheless, this hypothesis remains debatable before further investigation. Moreover, the crizotinib-induced STAT3 inhibition was supported by the research of Hamedani et al[ 29 ], which showed that crizotinib induces apoptosis through the downregulation of STAT3 phosphorylation in NPM-ALK positive anaplastic large cell lymphoma. However genetic inhibition of ALK was not employed in the original work.…”

Section: Discussionmentioning

confidence: 86%

Crizotinib induces autophagy through inhibition of the STAT3 pathway in multiple lung cancer cell lines

et al. 2015

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Autophagy is an evolutionarily conserved survival pathway in eukaryote and is frequently upregulated in cancer cells after chemotherapy or targeted therapy. Thus induction of autophagy has emerged as a drug resistance mechanism. In this study, we found that crizotinib induced a high level of autophagy in lung cancer cells through inhibition of STAT3. Ectopic expression of wild-type or constitutive activated STAT3 significantly suppressed the effect of crizotinib on autophagy. Interestingly, crizotinibmediated inhibition of STAT3 is in a step-wise manner. Firstly it inhibited cytoplasmic STAT3, which leads to the phosphorylation of EIF2A, then inhibited nuclear STAT3, which leads to the downregulation of BCL-2. Cell death induced by crizotinib was greatly enhanced after the inhibition of autophagy by the pharmacological inhibitors or shRNAs against Beclin-1. Moreover, the autophagy inhibitor HCQ significantly augmented the anti-tumor effect of crizotinib in a mouse xenograft model. In conclusion, crizotinib can induce cytoprotective autophagy by suppression of STAT3 in lung cancer cells. Thus, autophagy inhibition represents a promising approach to improve the efficacy of crizotinib in the treatment of targeted lung cancer patients.

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Section: Discussionmentioning

confidence: 86%

Crizotinib induces autophagy through inhibition of the STAT3 pathway in multiple lung cancer cell lines

et al. 2015

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“…Because the main mechanism of PEM is to inhibit nucleic acid synthesis, PEM-alone treatment is generally known to induce S-phase arrest [27]. On the other hand, ALK inhibitors, including crizotinib, increase the sub-G 1 apoptotic population in cells with the EML4-ALK rearrangement [28]. In our experiments, PEM increased the sub-G 1 population, similar to crizotinib, in EML4-ALK-rearranged cells, whereas S-phase arrest occurred in PEM-treated wild-type ALK cells.…”

Section: Discussionmentioning

confidence: 99%

Afatinib Overcomes Pemetrexed-Acquired Resistance in Non-Small Cell Lung Cancer Cells Harboring an EML4-ALK Rearrangement

Kwon

Kim

Sung

et al. 2019

Cells

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Background: The aim of this study is to elucidate the mechanisms of acquired resistance to pemetrexed in echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) rearranged non-small cell lung cancer. Methods: We analyzed the sensitivity to pemetrexed and the expression patterns of various proteins after pemetrexed treatment in the cell lines, A549, NCI-H460, NCI-H2228 harboring EML4-ALK variant 3, and NCI-H3122 harboring EML4-ALK variant 1. Pemetrexed-resistant cell lines were also generated through long-term exposure to pemetrexed. Results: The EML4-ALK variant 1 rearranged NCI-H3122 was found to be more sensitive than the other cell lines. Cell cycle analysis after pemetrexed treatment showed that the fraction of cells in the S phase increased in A549, NCI-H460, and NCI-H2228, whereas the fraction in the apoptotic sub-G1 phase increased in NCI-H3122. The pemetrexed-resistant NCI-H3122 cell line showed increased expression of EGFR and HER2 compared to the parent cell line, whereas A549 and NCI-H460 did not show this change. The pan-HER inhibitor afatinib inhibited this alternative signaling pathway, resulting in a superior cytotoxic effect in pemetrexed-resistant NCI-H3122 cell lines compared to that in the parental cells line. Conclusion: The activation of EGFR-HER2 contributes to the acquisition of resistance to pemetrexed in EML4-ALK rearranged non-small cell lung cancer. However, the inhibition of this alternative survival signaling pathway with RNAi against EGFR-HER2 and with afatinib overcomes this resistance.

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“…A wide range of RTKs phosphorylate STAT3 directly or via SRC kinase, and several studies have proven that blocking kinases such as KDR, PDGFRB, and ALK results in enhanced autophagy by subsequent inhibition of the STAT3 pathway (Table 3). 14,41,42,50,[74][75][76][77][78][79][80][81][82][83] Currently, several JAK-STAT inhibitors are being examined in clinical trials for cancer therapy. For example, in a phase II clinical trial to treat metastatic pancreatic cancer, ruxolitinib together with capecitabine showed a benefit for overall survival and progression-free survival compared with a placebo plus capecitabine used in second-line therapy, promoting the application of JAK-STAT inhibitors in cancer therapy.…”

Section: Implication Of Stat3-regulated Autophagy In Cancer Therapeuticsmentioning

confidence: 99%

The role of STAT3 in autophagy

et al. 2015

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Abbreviations: ALK, anaplastic lymphoma receptor tyrosine kinase; ATF4, activating transcription factor 4; BNIP3, BCL2/adenovirus E1B 19kDa interacting protein 3; CNTF, ciliary neurotrophic factor; COX8, cytochrome c oxidase subunit VIII; ConA, concanavalin A; CTSB, cathepsin B; CTSL, cathepsin L; CuB, cucurbitacin B; CYCS, cytochrome c, somatic; EGF, epidermal growth factor; EIF2A, eukaryotic initiation factor 2A, 65kDa; EIF2AK2, eukaryotic translation initiation factor 2-a kinase 2; ER, endoplasmic reticulum; ETC, electron transport chain; FOXO1/3, forkhead box O1/3; HDAC3, histone deacetylase 3; HIF1A, hypoxia inducible factor 1, a subunit (basic helix-loop-helix transcription factor); IL6, interleukin 6; IMM, inner mitochondrial membrane; KDR, kinase insert domain receptor; LMP, lysosomal membrane permeabilization; MAPK1, mitogen-activated protein kinase 1; MAP1LC3A, microtubule-associated protein 1 light chain 3 a; miRNA, microRNA; mitoSTAT3, mitochondrial STAT3; MLS, mitochondrial localization sequence; MMP14, matrix metallopeptidase 14 (membrane-inserted); NDUFA13, NADH dehydrogenase (ubiquinone) 1 a subcomplex, 13; NES, nuclear export signal; NFKB1, nuclear factor of kappa light polypeptide gene enhancer in B-cells 1; NLS, nuclear localization signal; PDGFRB, platelet-derived growth factor receptor, b polypeptide; PRKAA2, protein kinase, AMP-activated, a 2 catalytic subunit; PTPN2, protein tyrosine phosphatase, non-receptor type 2; PTPN6, protein tyrosine phosphatase, non-receptor type 6; PTPN11, protein tyrosine phosphatase, non-receptor type 11; ROS, reactive oxygen species; RTK, receptor tyrosine kinases; SH2, src homology 2; STAT3, signal transducer and activator of transcription 3 (acute-phase response factor); VHL, von Hippel-Lindau tumor suppressor, E3 ubiquitin protein ligase; XPO1, exportin 1.Autophagy is an evolutionarily conserved process in eukaryotes that eliminates harmful components and maintains cellular homeostasis in response to a series of extracellular insults. However, these insults may trigger the downstream signaling of another prominent stress responsive pathway, the STAT3 signaling pathway, which has been implicated in multiple aspects of the autophagic process. Recent reports further indicate that different subcellular localization patterns of STAT3 affect autophagy in various ways. For example, nuclear STAT3 fine-tunes autophagy via the transcriptional regulation of several autophagy-related genes such as BCL2 family members, BECN1, PIK3C3, CTSB, CTSL, PIK3R1, HIF1A, BNIP3, and microRNAs with targets of autophagy modulators. Cytoplasmic STAT3 constitutively inhibits autophagy by sequestering EIF2AK2 as well as by interacting with other autophagy-related signaling molecules such as FOXO1 and FOXO3. Additionally, the mitochondrial translocation of STAT3 suppresses autophagy induced by oxidative stress and may effectively preserve mitochondria from being degraded by mitophagy. Understanding the role of STAT3 signaling in the regulation of autophagy may provide insight into the cla...

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Crizotinib (PF-2341066) induces apoptosis due to downregulation of pSTAT3 and BCL-2 family proteins in NPM-ALK+ anaplastic large cell lymphoma

Cited by 23 publications

References 26 publications

Crizotinib induces autophagy through inhibition of the STAT3 pathway in multiple lung cancer cell lines

Crizotinib induces autophagy through inhibition of the STAT3 pathway in multiple lung cancer cell lines

Afatinib Overcomes Pemetrexed-Acquired Resistance in Non-Small Cell Lung Cancer Cells Harboring an EML4-ALK Rearrangement

The role of STAT3 in autophagy

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