Activating mutations in the RAS family of proto-oncogenes represent some of the leading causes of cancer. Unmitigated proliferation of cells harboring oncogenic RAS mutations is accompanied by a massive increase in cellular bioenergetic demands, which offers unique opportunities for therapeutic intervention. To withstand the steep requirements for metabolic intermediates, RAS-driven cancer cells enhance endolysosome and autophagosome biogenesis. By degrading cellular macromolecules into metabolites that can be used by biosynthetic pathways, endolysosomes permit continued proliferation and survival in otherwise detrimental conditions. We recently showed that human cancers with activating mutations in HRAS elevate the expression of MCOLN1, which encodes an endolysosomal cation channel called TRPML1. Increased TRPML1 activity in HRAS-driven cancer cells is needed for the restoration of plasma membrane cholesterol that gets collaterally internalized during endocytosis. Inhibition of TRPML1 or knockdown of MCOLN1 leads to mislocalization of cholesterol from the plasma membrane to endolysosomes, loss of oncogenic HRAS from the cell surface, and attenuation of downstream signaling. Here, we discuss the implications of our findings and suggest strategies to leverage pathways that impinge upon TRPML1 as novel anti-cancer treatments.

原癌基因RAS家族的激活突变是癌症的一些主要原因。携带致癌RAS突变的细胞的无节制增殖伴随着细胞生物能量需求的大幅增加，这为治疗干预提供了独特的机会。为了承受对代谢中间体的急剧需求，RAS 驱动的癌细胞增强了内溶酶体和自噬体的生物发生。通过将细胞大分子降解为可被生物合成途径使用的代谢物，内溶酶体允许在其他有害条件下持续增殖和存活。我们最近发现，具有HRAS激活突变的人类癌症会升高MCOLN1的表达，MC​​OLN1 编码称为 TRPML1 的内溶酶体阳离子通道。HRAS 驱动的癌细胞中 TRPML1 活性的增加是恢复质膜胆固醇（在内吞作用过程中被内在化）所必需的。抑制 TRPML1 或敲低MCOLN1会导致胆固醇从质膜错误定位到内溶酶体，细胞表面致癌 HRAS 丢失，以及下游信号传导减弱。在这里，我们讨论了我们的发现的意义，并提出了利用影响 TRPML1 的途径作为新型抗癌治疗的策略。