HSP110 promotes colorectal cancer growth through STAT3 activation

Abstract

Heat shock protein 110 (HSP110) is induced by different stresses and, through its anti-apoptotic and chaperoning properties, helps cells survive these adverse situations. In colon cancers, HSP110 is abnormally abundant. We have recently shown that colorectal cancer patients with microsatellite instability (MSI) had an improved response to chemotherapy because they harbor an HSP110-inactivating mutation (HSP110DE9). In this work, we used patient biopsies, human colorectal cancer cells grown in vitro and in vivo (xenografts), and intestinal crypts to demonstrate that HSP110 is also involved in colon cancer growth. We showed that HSP110 induces colon cancer cell proliferation and that this effect is associated with STAT3 activation, specifically an increase in STAT3 phosphorylation, nuclear translocation and transcription factor activity. STAT3 inhibition blocks the proliferative effect of HSP110. From a molecular standpoint, we demonstrated that HSP110 directly binds to STAT3, thereby facilitating its phosphorylation by JAK2. Finally, we showed a correlation between HSP110 expression and STAT3 phosphorylation in colon cancer patient samples. Thus, the expression of HSP110 in colon cancer contributes to STAT3-dependent tumor growth and the frequent inactivating mutation of this chaperone is probably an important event underlying the improved prognosis in colon cancer displaying MSI.

EGFR-mediated apoptosis via STAT3

“…Last, STAT3 is a well-documented regulator of cell growth, albeit more frequently having a positive effect. STAT3 has been associated with proliferative activity in numerous malignancies, including glioblastoma [59], non-small cell lung [60], and colorectal cancer [61]. In addition, STAT3-induced tumorigenesis is linked to its constitutive activity in certain cancer cells [62–64].…”

Dominant high expression of wild‐type HSP110 defines a poor prognostic subgroup of colorectal carcinomas with microsatellite instability: a whole‐section immunohistochemical analysis

“…It is also known that HSP110 overexpression is associated with nodal metastasis and an advanced stage in CRCs . According to a recent experimental study, HSP110 promotes the proliferation of colon cancer cells by directly activating STAT3 . Another recent study revealed that the HSP110 expression status is associated with differential polarization of tumor‐associated macrophages in colon cancer.…”

Hsp70 inhibitors: Implications for the treatment of colorectal cancer

“…BCL‐2‐associated athanogene (BAG) family is a group of six NEFs reported to regulate Hsp70 function either positively or negatively. A member of NEFs is Hsp110 or Hsp70‐binding protein 1 that increases cell survival through antiapoptotic properties . (c) The tetratricopeptide repeat co‐chaperones, including Hop and CHIP, bind to the C‐terminal EEVD motif.…”