Targeting an Autocrine Regulatory Loop in Cancer Stem-like Cells Impairs the Progression and Chemotherapy Resistance of Bladder Cancer

Abstract

Purpose: Cancer stem-like cells (CSCs) contribute to bladder cancer chemotherapy resistance and progression, but the associated mechanisms have not been elucidated. This study determined whether blocking an autocrine signaling loop in CSCs improves the therapeutic effects of cis-platinum on bladder cancer. Experimental Design: The expression of the epithelial marker OV6 and other markers in human bladder cancer specimens was examined by IHC. The CSC properties of magnetic-activated cell sorting (MACS)-isolated OV6 þ and OV6 À bladder cancer cells were examined. Molecular mechanisms were assessed through RNA-Seq, cytokine antibody arrays, co-immunoprecipitation (co-IP), chromatin immunoprecipitation (ChIP) and other assays. An orthotopic bladder cancer mouse model was established to evaluate the in vivo effects of a YAP inhibitor (verteporfin) and a PDGFR inhibitor (CP-673451) on the cis-platinum resistance of OV6 þ CSCs in bladder cancer. Results: Upregulated OV6 expression positively associated with disease progression and poor prognosis for bladder cancer patients. Compared with OV6 À cells, OV6 þ bladder cancer cells exhibited strong CSC characteristics, including self-renewal, tumor initiation in NOD/SCID mice, and chemotherapy resistance. YAP, which maintains the stemness of OV6 þ CSCs, triggered PDGFB transcription by recruiting TEAD1. Autocrine PDGF-BB signaling through its receptor PDGFR stabilized YAP and facilitated YAP nuclear translocation. Furthermore, blocking the YAP/TEAD1/ PDGF-BB/PDGFR loop with verteporfin or CP-673451 inhibited the cis-platinum resistance of OV6 þ bladder cancer CSCs in an orthotopic bladder cancer model. Conclusions: OV6 could be a helpful indicator of disease progression and prognosis for patients with bladder cancer, and targeting the autocrine YAP/TEAD1/PDGF-BB/PDGFR loop might serve as a remedy for cis-platinum resistance in patients with advanced bladder cancer.

Blocking the autocrine regulatory loop of Gankyrin/STAT3/CCL24/CCR3 impairs the progression and pazopanib resistance of clear cell renal cell carcinoma

“…The proliferation of ccRCC cells under the indicated conditions was detected using a CCK-8 kit (CK-04, Dojindo, Kumamoto, Kyushu, Japan) according to the manufacturer's instructions, as described in our previous study 19 . Prior to the assay, the medium was replaced with fresh medium, 10% v/v CCK-8 was added to each well, and the samples were incubated at 37°C for 2 h. The OD values at an absorbance of 450 nm were then measured using a microplate reader (EXL800, BioTek Instruments, Winooski, VT, USA).…”

RASSF1A inhibits PDGFB-driven malignant phenotypes of nasopharyngeal carcinoma cells in a YAP1-dependent manner

“…5f ) compared with those of IgG-treated RASSF1A-depleted CNE-1 cells. Long time of PDGF-BB treatment led to a spheroid-forming ability even higher than that of YAP1-expressing cells, possibly because of a autocrine PDGF-BB/PDGFR positive feedback loop 31 . Thus, RASSF1A mediated PDGFB inhibition via YAP1 inactivation in NPC cells.…”

“…YAP1 has been confirmed to trigger PDGFB transcription by recruiting TEAD1 31 . To further investigate the involvement of YAP1 in linking RASSF1A with PDGFB, we transiently knocked down YAP1 by using a pool of mixed siRNA in RASSF1A-depleted NPC cells, as confirmed by western blot analysis (Fig.…”

The Role of Photoactivated and Non-Photoactivated Verteporfin on Tumor

“…Likewise, Yu et al found that VP impaired the oncogenic properties of melanoma stem cells (Yu et al, 2014). VP sensitized the OV6+ bladder cancer stem cells to cisplatin by inhibiting the YAP/ TEAD1/PDGF-BB/PDGFR autocrine signaling pathway, which downregulated PDGFB and impaired PDGF-BB secretion (Wang J. K. et al, 2019). VP also downregulated the stem cell markers SOX2, NANOG, and OCT4 in transitional cell carcinoma of the bladder when used in combination with COX inhibitor (Ooki et al, 2018).…”

“…YAP transcriptionally activates IL-6, and stimulate IL-11 by up-regulating p65. Targeted inhibition of YAP by VP inhibited the binding between YAP and the IL-6 promoter, and downregulated IL-6 and IL-11 in endometrial cancer cells, resulting in lower proliferation rates ( Wang J. et al, 2019 ), increased sensitivity to adriamycin, and 45.36% decrease in tumor weight in the treated mice ( Bang et al, 2019 ).…”