Mutant Kras as a Biomarker Plays a Favorable Role in FL118-Induced Apoptosis, Reactive Oxygen Species (ROS) Production and Modulation of Survivin, Mcl-1 and XIAP in Human Bladder Cancer

Abstract

Tumor heterogeneity in key gene mutations in bladder cancer (BC) is a major hurdle for the development of effective treatments. Using molecular, cellular, proteomics and animal models, we demonstrated that FL118, an innovative small molecule, is highly effective at killing T24 and UMUC3 high-grade BC cells, which have Hras and Kras mutations, respectively. In contrast, HT1376 BC cells with wild-type Ras are insensitive to FL118. This concept was further demonstrated in additional BC and colorectal cancer cells with mutant Kras versus those with wild-type Kras. FL118 strongly induced PARP cleavage (apoptosis hallmark) and inhibited survivin, XIAP and/or Mcl-1 in both T24 and UMUC3 cells, but not in the HT1376 cells. Silencing mutant Kras reduced both FL118-induced PARP cleavage and downregulation of survivin, XIAP and Mcl-1 in UMUC3 cells, suggesting mutant Kras is required for FL118 to exhibit higher anticancer efficacy. FL118 increased reactive oxygen species (ROS) production in T24 and UMUC3 cells, but not in HT1376 cells. Silencing mutant Kras in UMUC3 cells reduced FL118-mediated ROS generation. Proteomics analysis revealed that a profound and opposing Kras-relevant signaling protein is changed in UMUC3 cells and not in HT1376 cells. Consistently, in vivo studies indicated that UMUC3 tumors are highly sensitive to FL118 treatment, while HT1376 tumors are highly resistant to this agent. Silencing mutant Kras in UMUC3 cell-derived tumors decreases UMUC3 tumor sensitivity to FL118 treatment. Together, our studies revealed that mutant Kras is a favorable biomarker for FL118 targeted treatment.

CircCA12 Promotes Malignant Process via Sponging miR-1184 and Upregulating RAS Family in Bladder Cancer

“…Recent bladder cancer studies have shown that genetic mutations in bladder epithelial cells frequently occur in FGFR3 , PIK3CA , and RAS (all associated with RAS signaling networks) ( Bockorny et al, 2018 ; Tsujino et al, 2019 ). In addition, a 2020 study demonstrated that the RAS mutation can be a favorable biomarker for diagnosing cancer patients ( Santha et al, 2020 ). With regard to the relationship between RAS oncogene and microRNAs (miRNAs), accumulating evidence suggests that some miRNAs directly target RAS signaling pathways, thereby impeding RAS-driven tumorigenesis ( Jinesh et al, 2018 ; Ding et al, 2020 ).…”

Long Non-Coding RNAs as Biomarkers and Therapeutic Targets in Sepsis

“…Compared with patients who died of sepsis, survivors also showed higher expression of lncRNA ENST00000504301.1, and lower expression of ENST00000452391.1 (104). Similarly, one study found that the expression of CRNDE was positively correlated with sequential organ failure assessment (SOFA), APACHEII score, and the expression of CRP and PCT (61).…”

“…These results reflected the study of Sun et al (1992) (60) who also found that inhibiting CRNDE could alleviate sepsis-induced kidney injury by blocking the activation of TLR3/NF-kB signaling. However, the study by Wang et al demonstrated that overexpression of CRNDE could downregulate the expression of miR-181a-5p, thereby increased the expression of peroxisome proliferator activated receptor a (PPARa), and finally protected kidney from more severe injury through promoting cell proliferation and preventing cell apoptosis (61). It is worth mentioning that Chen et al and Wu et al discovered that HOTAIR was upregulated in LPS-induced septic mice, and promoted monocyte apoptosis via sponging miR-211 and increasing TNF-a production through p65/NF-kB pathway (35,38).…”

“…However, the study by Wang et al. demonstrated that overexpression of CRNDE could downregulate the expression of miR-181a-5p, thereby increased the expression of peroxisome proliferator activated receptor α (PPARα), and finally protected kidney from more severe injury through promoting cell proliferation and preventing cell apoptosis ( 61 ). It is worth mentioning that Chen et al.…”

Kidney cancer biomarkers and targets for therapeutics: survivin (BIRC5), XIAP, MCL-1, HIF1α, HIF2α, NRF2, MDM2, MDM4, p53, KRAS and AKT in renal cell carcinoma

“…Additionally, TP53/p53 mutations or KRAS mutations are well known to be challenging treatment resistant factors. However, FL118 exhibited better anticancer efficacy in colorectal cancer (CRC) cells with mutant p53 [ 176 ], and our recent studies indicated that FL118 exhibited even better anticancer efficacy either in human bladder cancer cells with KRAS mutation or in human CRC cells with KRAS mutation in comparison with bladder cancer cells or CRC cells with wild type KRAS [ 186 , 187 ].…”