Abstract
Kinesins act as molecular microtubule-dependent motor proteins and have various important cellular functions related to cell division, intracellular transport, and membrane trafficking. However, the function of kinesin light chain 4 (KLC4) in cancer, especially radioresistance, has not been previously described. Thus, we investigated KLC4 function in lung cancer cells and radioresistant R-H460 cells by analyzing alterations in radiosensitivity after gene knockdown with siRNA and by evaluating cellular phenotypes and xenograft tumor growth. KLC4 was upregulated in human lung cancer cell lines. Moreover, in paired clinical specimens of lung cancer patients, KLC4 expression was significantly higher in tumor tissues than in paired adjacent normal tissues. Fluorescence-activated cell sorting (FACS) analysis showed that apoptosis rates and cleaved poly (ADP-ribose) polymerase (PARP) and cleaved caspase-3 levels in KLC4-knockdown lung cancer cells were significantly increased compared with those in control cells. Colony formation decreased as the radiation dose increased in KLC4-knockdown lung cancer cells, demonstrating an essential role for KLC4 in radioresistance. Importantly, KLC4 silencing suppressed tumor growth in an in vivo xenograft model, accompanied by increased apoptosis. Finally, KLC4-knockdown cells exhibited impaired mitochondrial respiration, increased mitochondrial reactive oxygen species production, and enhanced mitochondrial calcium uptake, resulting in mitochondrial dysfunction. Thus, KLC4 as a kinesin superfamily-targeted therapy may represent a novel, effective anticancer strategy, particularly for patients showing radioresistance.
Highlights
Lung cancer is the second most commonly diagnosed cancer and has the highest mortality rate of all types of cancer worldwide[1]
kinesin light chain 4 (KLC4) is involved in radioresistance and tumorigenesis of lung cancer To identify radioresistant lung cancer cells, we assessed the cell death after 10 Gy treatment of H460, radioresistant H460 (R-H460), A549 and H1299 cell lines using Fluorescence-activated cell sorting (FACS) analysis (Fig. 1a)
The results showed that the KLC4 level was correlated with radioresistant tendency in the human lung cancer cell lines (Fig. 1b, c)
Summary
Lung cancer is the second most commonly diagnosed cancer and has the highest mortality rate of all types of cancer worldwide[1]. The current best therapies for lung cancer patients achieve anz overall 5-year survival rate of 16 and 6% for non-small cell lung cancer and small cell lung cancer[2], respectively. Radiotherapy (RT) is a promising treatment for both early-stage and advancedstage lung cancer patients, some patients with a high surgical risk experience recurrence and metastatic diseases despite receiving RT treatment[3,4]. A major contributor to poor outcomes is radioresistance; intrinsic (primary) radioresistance involves a subpopulation of clonogenic cells within the tumor[5], while acquired radioresistance occurs during RT treatment[6]. The mechanisms of cancer radioresistance are affected by several factors that significantly affect radiation efficiency.
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