XBP1 as a novel molecular target to attenuate drug resistance in hepatocellular carcinoma

ABSTRACT

Introduction

Despite improvements in clinical management of hepatocellular carcinoma (HCC), prognosis remains poor with a 5-year survival rate less than 40%. Drug resistance in HCC makes it challenging to treat; therefore, it is imperative to develop new therapeutic strategies. Higher expression of X-box binding protein 1 (XBP1) in tumor cells is highly correlated with poor prognosis. In tumor cells, XBP1 modulates the unfolded protein response (UPR) to restore homeostasis in endoplasmic reticulum. Targeting XBP1 could be a promising therapeutic strategy to overcome HCC resistance and improve the survival rate of patients.

Areas covered

This review provides the recent evidence that indicates XBP1 is involved in HCC drug resistance via DNA damage response, drug inactivation, and inhibition of apoptosis. In addition, the potential roles of XBP1 in inducing resistance in HCC cells were highlighted, and we showed how its inhibition could sensitize tumor cells to controlled cell death.

Expert opinion

Due to the diversity in molecular mechanism of multidrug-resistance, targeting one specific pathway is inadequate. XBP1 inhibition could be a potential therapeutic target to overcome tumor chemoresistance. The main function of this transcription factor in HCC treatment response is an attractive area for further studies and should be discussed more.

KEYWORDS:

• Hepatocellular carcinoma
• drug resistance
• ER stress
• unfolded protein response
• XBP1

Article highlights

• Higher expression of XBP1 is associated with poor prognosis in HCC patients.

• Greater XBP1 splicing results in cell transition from UPR driven apoptosis to cell survival.

• XBP1 targets various genes involved in drug resistance.

• Silencing XBP1 could promote sensitivity to anticancer agents in solid tumors.

• Pharmacological and genetic inhibition of XBP1 are methods using in recent studies to attenuate tumor progression.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Author contribution

Z.H. and D.H. and M.V. developed the concept. Z.H. and M.V. drafted the manuscript.

Correction Statement

This article has been corrected with minor changes. These changes do not impact the academic content of the article.

Additional information

Funding

This paper was not funded.