The mechanical force of minority cells modulates the tumor taxol-resistance and progression

Cancer is a leading cause of death worldwide. The chemotherapy is one of a major treatment for cancer. However, resistance to chemotherapeutic agents is still a crucial problem in cancer therapies. Majority drug resistance results from the accumulation of mutation of genes in the minority-resistant cells. The mechanism underlying the emergence and the development of cancer resistance from minority-resistant cells has not been fully elucidated. Here, we revealed that minority taxol-resistant cancer cells (MRCs) with enhanced mechanical force can transmit the high force to surrounding sensitive cells through force transducer merlin, and thus enhancing the contraction and adhesion strength of tumor cells (termed as mechanoassimilation), which eventually accelerates the development of drug resistance and tumor progression in vivo. In addition, disturbance and reduction of mechanoassimilation in tumor leads them sensitive to taxol again in vitro and in vivo, which also provide a preliminary indication of MRC contribution in drug-resistance and malignancy development through mechanoassimilation, and offer a new opportunity for cancer therapy by targeting the tumor mechanics.

Targeting tumor-macrophage interaction via the Notch2-Jag1 axis reverses tumor resistance to paclitaxel

Taxanes are widely used in chemotherapy, but intrinsic and acquired resistance limit the clinical outcomes. Studies showed tumor interaction with suppressive macrophages plays a key role in taxane resistance, yet therapeutic strategies that deplete or repolarize macrophages are challenging. Here we uncovered a novel tumor-macrophage interaction via Notch2-Jag1 justacrine signaling that can be targeted to sensitize paclitaxel response without affecting the broad macrophage functions. Using translatome profiling, we identified Notch2 upregulation during taxol-induced prolonged mitosis. Notch2 was subsequently activated in the post-mitotic G1 phase by Jag1 expressed on neighboring macrophages, which promoted tumor cell survival by upregulating p38 and anti-apoptotic proteins. Notch2 also upregulated cytokines that further recruited Jag1-expressing macrophages. By targeting this Notch2-Jag1 interaction with a pan-Notch inhibitor, RO4929097, taxol resistance was significantly attenuated in multiple mouse tumor models. Our results point to combining Notch inhibitor with taxane as an effective strategy to selectively disrupt tumor-macrophage interaction underlying chemoresistance.

Circular RNA circ_0006168 enhances Taxol resistance in esophageal squamous cell carcinoma by regulating miR-194-5p/JMJD1C axis

Background Chemoresistance is one of the major obstacles for cancer therapy in the clinic. Circular RNAs (circRNAs) are involved in the pathogenesis of esophageal squamous cell carcinoma (ESCC) and chemoresistance. This study aimed to explore the role and molecular mechanism of circ_0006168 in Taxol resistance of ESCC. Methods The expression levels of circ_0006168, microRNA-194-5p (miR-194-5p) and jumonji domain containing 1C (JMJD1C) were measured by quantitative real-time polymerase chain reaction (qRT-PCR) or western blot. The half-inhibition concentration (IC50) value of Taxol was evaluated by Cell Counting Kit-8 (CCK-8) assay. Cell proliferation was evaluated by CCK-8 and colony formation assays. Cell migration and invasion were detected by transwell assay. Cell apoptosis was determined by flow cytometry. The interaction between miR-194-5p and circ_0006168 or JMJD1C was predicted by bioinformatics analysis (Circinteractome and TargetScan) and verified by dual-luciferase reporter and RNA Immunoprecipitation (RIP) and RNA pull-down assays. The mice xenograft model was established to investigate the roles of circ_0006168 in vivo. Results Circ_0006168 and JMJD1C were upregulated and miR-194-5p was downregulated in ESCC tissues, ESCC cells, and Taxol-resistant cells. Functionally, knockdown of circ_0006168 or JMJD1C increased Taxol sensitivity of ESCC in vitro via inhibiting cell proliferation, migration and invasion, and promoting apoptosis. Moreover, circ_0006168 could directly bind to miR-194-5p and JMJD1C was verified as a direct target of miR-194-5p. Mechanically, circ_0006168 was a sponge of miR-194-5p to regulate JMJD1C expression in ESCC cells. Furthermore, JMJD1C overexpression reversed the promotive effect of circ_0006168 knockdown on Taxol sensitivity. Besides, circ_0006168 silence suppressed tumor growth in vivo. Conclusion Circ_0006168 facilitated Taxol resistance in ESCC by regulating miR-194-5p/JMJD1C axis, providing a promising therapeutic target for ESCC chemotherapy.

Mdivi-1 induces spindle abnormalities and augments taxol cytotoxicity in MDA-MB-231 cells

Taxol is a first-line chemotherapeutic for numerous cancers, including the highly refractory triple-negative breast cancer (TNBC). However, it is often associated with toxic side effects and chemoresistance in breast cancer patients, which greatly limits the clinical utility of the drug. Hence, compounds that act in concert with taxol to promote cytotoxicity may be useful to improve the efficacy of taxol-based chemotherapy. In this study, we demonstrated that mdivi-1, a putative inhibitor of mitochondrial fission protein Drp1, enhances the anticancer effects of taxol and overcomes taxol resistance in a TNBC cell line (MDA-MB-231). Not only did mdivi-1 induce mitotic spindle abnormalities and mitotic arrest when used alone, but it also enhanced taxol-induced antimitotic effects when applied in combination. In addition, mdivi-1 induced pronounced spindle abnormalities and cytotoxicity in a taxol-resistant cell line, indicating that it can overcome taxol resistance. Notably, the antimitotic effects of mdivi-1 were not accompanied by prominent morphological or functional alterations in mitochondria and were Drp1-independent. Instead, mdivi-1 exhibited affinity to tubulin at μM level, inhibited tubulin polymerization, and immediately disrupted spindle assembly when cells entered mitosis. Together, our results show that mdivi-1 associates with tubulin and impedes tubulin polymerization, actions which may underlie its antimitotic activity and its ability to enhance taxol cytotoxicity and overcome taxol resistance in MDA-MB-231 cells. Furthermore, our data imply a possibility that mdivi-1 could be useful to improve the therapeutic efficacy of taxol in breast cancer.

High Expression of RIPK2 is Associated with Taxol Resistance in Serous Ovarian Cancer

BackgroundTaxol resistance of serous ovarian cancer is responsible for its poor prognosis, yet the underlying mechanism was still poorly understood. Thus, we probed the mechanism of taxol resistance in serous ovarian cancer with multiple bioinformatic methods to provide novel insights for potential therapy. MethodsThe differentially expressed genes (DEGs) and their relationship with overall survival (OS) and progress-free interval (PFI) of ovarian cancer patients were analyzed using gene expression datasets from the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). The role of receptor interacting serine/threonine kinase 2 (RIPK2) was validated by identifying its co-expressed genes, making function analysis and generating protein-protein network (PPI). Single-sample GSEA (ssGSEA) method was used to explore the immune infiltration and genomic alterations of RIPK2 was also analyzed via cBio Cancer Genomics Portal (cBioProtal).ResultsRIPK2 was highly expressed in taxol resistant ovarian cancer cell lines, while its high expression was also linked with OS and PFI in serous ovarian cancer patients. The PPI network analysis and pathway analysis demonstrated that RIPK2 might take part in positive regulation of NF-κB transcription factor activity. Different expression level of RIPK2 was related to tumor microenvironment alteration, which might participate in formation of taxol resistance.ConclusionsOur studies suggested that high expression of RIPK2 was related to taxol resistance in serous ovarian cancer, while RIPK2 induced taxol resistance through NOD1/RIPK2/NF-κB inflammatory pathway activation and tumor microenvironment changes.

The nature of the modification at position 37 of tRNAPhe correlates with acquired taxol resistance

Acquired drug resistance is a major obstacle in cancer therapy. Recent studies revealed that reprogramming of tRNA modifications modulates cancer survival in response to chemotherapy. However, dynamic changes in tRNA modification were not elucidated. In this study, comparative analysis of the human cancer cell lines and their taxol resistant strains based on tRNA mapping was performed by using UHPLC–MS/MS. It was observed for the first time in all three cell lines that 4-demethylwyosine (imG-14) substitutes for hydroxywybutosine (OHyW) due to tRNA-wybutosine synthesizing enzyme-2 (TYW2) downregulation and becomes the predominant modification at the 37th position of tRNAphe in the taxol-resistant strains. Further analysis indicated that the increase in imG-14 levels is caused by downregulation of TYW2. The time courses of the increase in imG-14 and downregulation of TYW2 are consistent with each other as well as consistent with the time course of the development of taxol-resistance. Knockdown of TYW2 in HeLa cells caused both an accumulation of imG-14 and reduction in taxol potency. Taken together, low expression of TYW2 enzyme promotes the cancer survival and resistance to taxol therapy, implying a novel mechanism for taxol resistance. Reduction of imG-14 deposition offers an underlying rationale to overcome taxol resistance in cancer chemotherapy.