Heat shock protein 47 promotes tumor survival and therapy resistance by modulating AKT signaling via PHLPP1 in colorectal cancer

Yijye Chern, Peter Zhang, Hyelim Ju, et al.

Abstract


Objective: Heat shock protein 47 (HSP47) is a collagen-specific molecular chaperone that facilitates collagen maturation. Its role incancer remains largely unknown. In this study, we investigated the roles of HSP47 in colorectal cancer (CRC) and therapy resistance.

Methods: Expression of HSP47 in CRC tissues was examined (1) in paired human CRC/adjacent normal tissues, using realtime quantitative reverse transcription polymerase chain reaction (qRT-PCR), The Cancer Genome Atlas (TCGA) database, and22 independent microarray databases (curated CRC). In vitro studies on several CRC cell lines (HCT116, RKO and CCL228)with modulated HSP47 expression were conducted to assess cell viability and apoptosis (TUNEL assay and caspase-3/-7) duringexposure to chemotherapy. AKT signaling and co-immunoprecipitation studies were performed to examine HSP47 and PHLPP1interaction. In vivo studies using tumor xenografts were conducted to assess the effects of HSP47 modulation on tumor growthand therapy response.

Results: HSP47 was upregulated in CRC and was associated with poor prognosis in individuals with CRC. In vitro, HSP47overexpression supported the survival of CRC cells, whereas its knockdown sensitized cells to 5-fluorouracil (5-FU). HSP47promoted survival by inhibiting apoptosis, enhancing AKT phosphorylation, and decreasing expression of the AKT-specificphosphatase PHLPP1 when cells were exposed to chemotherapy. These effects were partly results of the interaction between HSP47and PHLPP1, which decreased PHLPP1 stability and led to more persistent AKT activity. In vivo, HSP47 supported tumor growthdespite 5-FU treatment.

Conclusions: HSP47 supports the growth of CRC tumors and suppresses the efficacy of chemotherapy via modulation of AKTsignaling.

Cite this article as: Chern Y, Zhang P, Ju H, Tai TI. Heat shock protein 47promotes tumor survival and therapy resistance by modulating AKT signalingvia PHLPP1 in colorectal cancer. Cancer Biol Med. 2020; 17: 343-356. doi:10.20892/j.issn.2095-3941.2019.0261


Keywords


HSP47; AKT; PHLPP1; colorectal cancer; resistance

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