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Quiescent hepatic stellate cells induce toxicity and sensitivity to doxorubicin in cancer cells through a caspase‐independent cell death pathway: Central role of apoptosis‐inducing factor

Hepatocellular carcinoma (HCC) is a major health problem worldwide and in the United States as its incidence has increased substantially within the past two decades. HCC therapy remains a challenge, primarily due to underlying liver disorders such as cirrhosis that determines treatment approach and efficacy. Activated hepatic stellate cells (A‐HSCs) are the key cell types involved in hepatic fibrosis/cirrhosis. A‐HSCs are important constituents of HCC tumor microenvironment (TME) and support tumor growth, chemotherapy resistance, cancer cell migration, and escaping immune surveillance. This makes A‐HSCs an important therapeutic target in hepatic fibrosis/cirrhosis as well as in HCC. Although many studies have reported the role of A‐HSCs in cancer generation and investigated the therapeutic potential of A‐HSCs reversion in cancer arrest, not much is known about inactivated or quiescent HSCs (Q‐HSCs) in cancer growth or arrest. Here we report that Q‐HSCs resist cancer cell growth by inducing cytotoxicity and enhancing chemotherapy sensitivity. We observed that the conditioned media from Q‐HSCs (Q‐HSCCM) induces cancer cell death through a caspase‐independent mechanism that involves an increase in apoptosis‐inducing factor expression, nuclear localization, DNA fragmentation, and cell death. We further observed that Q‐HSCCM enhanced the efficiency of doxorubicin, as measured by cell viability assay. Exosomes present in the conditioned media were not involved in the mechanism, which suggests the role of other factors (proteins, metabolites, or microRNA) secreted by the cells. Identification and characterization of these factors are important in the development of effective HCC therapy.