The MIP‐1α autocrine loop contributes to decreased sensitivity to anticancer drugs

Noguchi

et al. 2019

Cancers

RAS and BRAF-mutated colorectal cancers are associated with resistance to chemotherapy and poor prognosis, highlighting the need for new therapeutic strategies. Although these cancers sometimes respond to mitogen activated protein kinase kinase (MEK) inhibitor treatment, they often acquire resistance via mechanisms, which are poorly understood. Here, we investigated the mechanism of MEK inhibitor resistance in primary- and acquired-resistant cells. Cell viability was examined using the trypan blue dye exclusion assay. Protein expression was analyzed by western blotting. Somatic mutations in colorectal cancer cells were investigated using the polymerase chain reaction array. PD0325901 and trametinib induced cell death in LoVo and Colo-205 cells but not in DLD-1 and HT-29 cells, which have a PIK3CA mutation constitutively activating Akt and NF-κB. Treatment with PD0325901 and trametinib suppressed ERK1/2 activation in all four cell lines but only induced Akt and NF-κB activation in DLD-1 and HT-29 cells. Inhibition of Akt but not NF-κB, overcame MEK inhibitor resistance in DLD-1 and HT-29 cells. Acquired-resistant LoVo/PR, Colo-205/PR and LoVo/TR cells have constitutively active Akt due to a M1043V mutation in the kinase activation loop of PIK3CA and Akt inhibitor resensitized these cells to MEK inhibitor. These results demonstrate that the overactivation of Akt plays a critical role in MEK inhibitor primary and acquired resistance and implicate combined Akt/MEK inhibition as a potentially useful treatment for RAS/BRAF-mutated colorectal cancer.

Section: Discussionmentioning

confidence: 45%

“…LoVo and Colo-205 cells with acquired resistance to PD0325901 (LC Laboratories, Woburn, MA, USA) or trametinib (LC Laboratories) (LoVo/PR, Colo-205/PR and LoVo/TR) were generated as previously described [37,[51][52][53][54][55].…”

Section: Cell Culturementioning

confidence: 99%

Overactivation of Akt Contributes to MEK Inhibitor Primary and Acquired Resistance in Colorectal Cancer Cells

Noguchi

et al. 2019

Cancers

“…P values of < 0.05 were regarded significant. Drug interactions were measured based on the combination index (CI), as previously described [24,39].…”

Section: Discussionmentioning

confidence: 99%

“…Bcl-2 and Bcl-XL, a member of anti-apoptotic Bcl-2 family proteins, suppress apoptosis by involving mitochondrial outer membrane permeability [19], yet inhibitor of apoptosis (IAP) family proteins do so by inhibiting caspase activity [20,21]. Most anti-cancer drugs suppress tumor proliferation by inducing apoptosis, hence the overexpression of anti-apoptotic proteins results in drug resistance [22][23][24][25]. To understand drug resistance, further studies are required on the underlying intracellular signaling pathways.…”

Section: Introductionmentioning

confidence: 99%

Dasatinib reverses drug resistance by downregulating MDR1 and Survivin in Burkitt lymphoma cells

Tabata

BMC Complement Med Ther

et al. 2020

Self Cite

Background: Current chemotherapies for Burkitt lymphoma (BL) have dramatically improved its clinical outcome. However, chemoresistance can lead to chemotherapy failure and very poor prognosis; thus, novel strategies are urgently required for patients with drug-resistant BL. To investigate the mechanisms underlying drug resistance in BL, we established drug-resistant BL cell lines: HS-Sultan/ADM (adriamycin-resistant), HS-Sultan/VCR (vincristineresistant), HS-Sultan/DEX (dexamethasone-resistant), and HS-Sultan/L-PAM (melphalan-resistant). Methods: Drug transporter and survival factor expression were investigated the using western blotting and real time polymerase chain reaction. Cell survival was analyzed by trypan blue dye exclusion method. Results: The established cell lines acquired cross-resistance to adriamycin, vincristine, dexamethasone, and melphalan and exhibited 50% inhibitory concentration values 106-, 40-, 81-, and 45-fold higher than the parental cell lines, respectively. We found that protein and mRNA expression of MDR1 and Survivin were higher in drug-resistant BL cells than in the parent cells. Treatment with verapamil, an MDR1 inhibitor, or Survivin siRNA alongside each anti-cancer drug suppressed the proliferation of all drug-resistant BL cells. Src kinase activity was higher in all resistant cell lines than the parental cells; suppressing Src with dasatinib restored drug sensitivity by reducing MDR1 and Survivin expression. Conclusions: MDR1 and Survivin upregulation are responsible for resistance to conventional drugs and dasatinib can restore drug sensitivity by reducing MDR1 and Survivin expression in drug-resistant BL cells. Src inhibitors could therefore be a novel treatment strategy for patients with drug resistant BL.

“…*P < 0.01 vs. RPMI8226 untreated cells, # P < 0.01 vs. RPMI8226/L-PAM untreated cells (ANOVA with Dunnett's test) inflammatory protein 1α (MIP-1α) or tumor necrosis factor α (TNFα) promote c-Src activation via binding to specific receptors in cancer cells [41]. In addition, activation of ERK1/2, Akt, and/or NF-κB by MIP-1α and/or TNFα autocrine loop is associated with melphalan resistance in MM cells [40,42]. These findings indicated that activation of ERK1/2, Akt, and NF-κB contributes to melphalan resistance in MM cells.…”

Section: Discussionmentioning

confidence: 99%

Overexpression of HIF-1α contributes to melphalan resistance in multiple myeloma cells by activation of ERK1/2, Akt, and NF-κB

Laboratory Investigation

Tomonari

et al. 2019

Self Cite

Multiple myeloma (MM) commonly displays multidrug resistance and is associated with poor prognosis. Therefore, it is important to identify the mechanisms by which MM cells develop multidrug resistance. Our previous study showed that multidrug resistance is correlated with overexpression of multidrug resistance protein 1 (MDR1) and Survivin, and downregulation of Bim expression in melphalan-resistant RPMI8226/L-PAM cells; however, the underlying mechanism of multidrug resistance remains unclear. In the present study, we investigated the mechanism of multidrug resistance in melphalan-resistant cells. We found that RPMI8226/L-PAM and ARH-77/L-PAM cells showed increased phosphorylation of extracellular signal-regulated protein kinase 1/2 (ERK1/2) and Akt, and nuclear localization of nuclear factor κB (NF-κB). The combination of ERK1/2, Akt, and NF-κB inhibitors with melphalan reversed melphalan resistance via suppression of Survivin expression and enhanced Bim expression in melphalan-resistant cells. In addition, RPMI8226/L-PAM and ARH-77/L-PAM cells overexpressed hypoxia-inducible factor 1α (HIF-1α) via activation of ERK1/2, Akt, and NF-κB. Moreover, suppression of HIF-1α by echinomycin or HIF-1α siRNA resensitized RPMI8226/L-PAM cells to melphalan through downregulation of Survivin expression and upregulation of Bim expression. These results indicate that enhanced Survivin expression and decreased Bim expression by HIF-1α via activation of ERK1/2, Akt, and NF-κB play a critical role in melphalan resistance. Our findings suggest that HIF-1α, ERK1/2, Akt, and NF-κB inhibitors are potentially useful as anti-MDR agents for the treatment of melphalan-resistant MM.