Inhibition of hsp27 and hsp40 potentiates 5-fluorouracil and carboplatin mediated cell killing in hepatoma cells

Abstract

Heat shock proteins (Hsps) modulate several cellular functions and are

ubiquitously present in cell. Here, we investigated alterations in the

expression of Hsps and explored functional consequences of the same.

Moreover, effect of quercetin (Qctn), an inhibitor of Hsps, on

chemotherapeutic drugs treatment in hepatoma cells Hep3B and HepG2 was

investigated. We for the first time report that 5-fluorouracil (5-FU) and

carboplatin specifically induce expression of Hsp40 in addition to Hsp27 in

Hep3B and HepG2 cells. Induction of Hsps following exposure to sub lethal

dose of drugs is a cellular challenge to survival. However, under lethal

environmental conditions with reduced cell viability, cells fail to sustain the

induction of survival proteins, Hsp27 and Hsp40.  Though Qctn itself, to

certain extent is cytotoxic to cells, it potentiates the pro-apoptotic action of 5-

FU and carboplatin, by inhibiting expression of Hsps. The increased cell killing

correlates with decreased levels of procaspase-3. Furthermore, siRNA

mediated knockdown of Hsp27 and Hsp40 diminishes survival of drugs

exposed cells. Altogether, our data provides clear evidence that Hsp27 and

40 promote cell survival and inhibition of their expression does not allow cells

to adapt to drug exposure and survive. Collectively, our novel findings on

compelling action of 5-FU or carboplatin following knockdown of Hsp40 and

that of Hsp27 highlights their strategic implications towards an effective

therapy against HCC.